Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs

Dawn Merton Boothe Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849.

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 DVM, PhD, DACVIM, DACVCP
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Curtis Dewey Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850.

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 DVM, MS, DACVS, DACVIM
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David Mark Carpenter Department of Mathematics and Statistics, College of Sciences and Mathematics, Auburn University, Auburn, AL 36849.

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 PhD
DOI:
https://doi.org/10.2460/javma.240.9.1073
Volume/Issue:
Volume 240: Issue 9
Online Publication Date:
01 May 2012
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Abstract

Objective—To compare efficacy and safety of treatment with phenobarbital or bromide as the first-choice antiepileptic drug (AED) in dogs.

Design—Double-blinded, randomized, parallel, clinical trial.

Animals—46 AED-naïve dogs with naturally occurring epilepsy.

Procedures—Study inclusion was based on age, history, findings on physical and neurologic examinations, and clinicopathologic test results. For either phenobarbital treatment (21 dogs) or bromide treatment (25), a 7-day loading dose period was initiated along with a maintenance dose, which was adjusted on the basis of monthly monitoring. Efficacy and safety outcomes were compared between times (baseline and study end [generally 6 months]) and between drugs.

Results—Phenobarbital treatment resulted in eradication of seizures (17/20 [85%]) significantly more often than did bromide (12/23 [52%]); phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88 ± 34%), compared with bromide (49 ± 75%). Seizure activity worsened in 3 bromide-treated dogs only. In dogs with seizure eradication, mean ± SD serum phenobarbital concentration was 25 ± 6 μg/mL (phenobarbital dosage, 4.1 ± 1.1 mg/kg [1.9 ± 0.5 mg/lb], PO, q 12 h) and mean serum bromide concentration was 1.8 ± 0.6 mg/mL (bromide dosage, 31 ± 11 mg/kg [14 ± 5 mg/lb], PO, q 12 h). Ataxia, lethargy, and polydipsia were greater at 1 month for phenobarbital-treated dogs; vomiting was greater for bromide-treated dogs at 1 month and study end.

Conclusions and Clinical Relevance—Both phenobarbital and bromide were reasonable first-choice AEDs for dogs, but phenobarbital was more effective and better tolerated during the first 6 months of treatment.

Abstract

Objective—To compare efficacy and safety of treatment with phenobarbital or bromide as the first-choice antiepileptic drug (AED) in dogs.

Design—Double-blinded, randomized, parallel, clinical trial.

Animals—46 AED-naïve dogs with naturally occurring epilepsy.

Procedures—Study inclusion was based on age, history, findings on physical and neurologic examinations, and clinicopathologic test results. For either phenobarbital treatment (21 dogs) or bromide treatment (25), a 7-day loading dose period was initiated along with a maintenance dose, which was adjusted on the basis of monthly monitoring. Efficacy and safety outcomes were compared between times (baseline and study end [generally 6 months]) and between drugs.

Results—Phenobarbital treatment resulted in eradication of seizures (17/20 [85%]) significantly more often than did bromide (12/23 [52%]); phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88 ± 34%), compared with bromide (49 ± 75%). Seizure activity worsened in 3 bromide-treated dogs only. In dogs with seizure eradication, mean ± SD serum phenobarbital concentration was 25 ± 6 μg/mL (phenobarbital dosage, 4.1 ± 1.1 mg/kg [1.9 ± 0.5 mg/lb], PO, q 12 h) and mean serum bromide concentration was 1.8 ± 0.6 mg/mL (bromide dosage, 31 ± 11 mg/kg [14 ± 5 mg/lb], PO, q 12 h). Ataxia, lethargy, and polydipsia were greater at 1 month for phenobarbital-treated dogs; vomiting was greater for bromide-treated dogs at 1 month and study end.

Conclusions and Clinical Relevance—Both phenobarbital and bromide were reasonable first-choice AEDs for dogs, but phenobarbital was more effective and better tolerated during the first 6 months of treatment.

Contributor Notes

This study was implemented at Texas A&M University's Texas Veterinary Medical Center but included the participation of referral practitioners throughout the United States.

Supported by the Canine Health Foundation and the American Kennel Club.

Presented as a poster at the 20th American College of Veterinary Internal Medicine Annual Forum, Dallas, May 2002.

Address correspondence to Dr. Boothe (boothdm@auburn.edu).
Cover Journal of the American Veterinary Medical Association
Journal of the American Veterinary Medical Association
Publication Date:
01 May 2012
  • 1.

    Parent JM. Clinical management of canine seizures. Vet Clin North Am Small Anim Pract 1988; 18:947–965.

  • 2.

    Lane SB, Bunch SE. Medical management of recurrent seizures in dogs and cats. J Vet Intern Med 1990; 4:26–39.

  • 3.

    Pearce LK. Potassium bromide as an adjunct to phenobarbital for the management of uncontrolled seizures in dogs. Prog Vet Neurol 1990; 1:195–101.

    • Search Google Scholar
    • Export Citation
  • 4.

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

  • 5.

    Podell M. Seizures in dogs. Vet Clin North Am Small Anim Pract 1996; 26:779–809.

  • 6.

    Trepanier LA. Use of bromide as an anticonvulsant for dogs with epilepsy. J Am Vet Med Assoc 1995; 207:163–166.

  • 7.

    Boothe DM. Anticonvulsant and other neurologic therapies. In: Boothe DM, ed. Small animal clinical pharmacology and therapeutics. Philadelphia: WB Saunders Co, 2001;431–456.

    • Search Google Scholar
    • Export Citation
  • 8.

    Dewey CW. Anticonvulsant therapy in dogs and cats. Vet Clin North Am Small Anim Pract 2006; 36:1107–1127.

  • 9.

    Pedersoli WM, Wike JS, Ravis WR. Pharmacokinetics of single doses of phenobarbital given intravenously and orally to dogs. Am J Vet Res 1987; 48:679–683.

    • Search Google Scholar
    • Export Citation
  • 10.

    Ravis WR, Pedersoli WM, Wike JS. Pharmacokinetics of phenobarbital in dogs given multiple doses. Am J Vet Res 1989; 50:1343–1347.

  • 11.

    Trepanier LA, Babish JG. Pharmacokinetic properties of bromide in dogs after the intravenous and oral administration of single doses. Res Vet Sci 1995; 58:248–251.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Cunningham JG, Haidukewych D, Jensen HA. Therapeutic serum concentrations of primidone and its metabolites, phenobarbital and pheynlethylmalonamide in epileptic dogs. J Am Vet Med Assoc 1983; 182:1091–1094.

    • Search Google Scholar
    • Export Citation
  • 13.

    Morton DJ, Honhold N. Effectiveness of a therapeutic drug monitoring service as an aid to the control of canine seizures. Vet Rec 1988; 122:346–349.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Levitski RE, Trepanier LA. Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy. J Am Vet Med Assoc 2000; 217:200–204.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Grewal MS, Swinyard EA, Jensen HV, et al. Correlation between anticonvulsant activity and plasma concentration of bromide. J Pharmacol Exp Ther 1954; 112:109–115.

    • Search Google Scholar
    • Export Citation
  • 16.

    Trepanier LA, Van Schoick A, Schwark WS, et al. Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992–1996). J Vet Intern Med 1998; 213:1449–1453.

    • Search Google Scholar
    • Export Citation
  • 17.

    US Pharmacopeia. Bromide compounding monograph. In: United States pharmacists' pharmacopeia 2008–2009. Rockville, Md: US Pharmacopeial Convention, 2009.

    • Search Google Scholar
    • Export Citation
  • 18.

    Dayrell-Hart B, Steinberg SA, VanWinkle TJ, et al. Hepatotoxicity of phenobarbital in dogs: 18 cases (1985–1989). J Am Vet Med Assoc 1991; 199:1060–1066.

    • Search Google Scholar
    • Export Citation
  • 19.

    Gaskill CL, Miller LM, Mattoon JS, et al. Liver histopathology and liver and serum alanine aminotransferase and alkaline phosphatase activities in epileptic dogs receiving phenobarbital. Vet Pathol 2005; 42:147–160.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Muller PB, Taboada J, Hosgood G, et al. Effects of long-term phenobarbital treatment on the liver in dogs. J Vet Intern Med 2000; 15:165–171.

    • Search Google Scholar
    • Export Citation
  • 21.

    Jacobs G, Calvert C, Kaufman A. Neutropenia and thrombocytopenia in three dogs treated with anticonvulsants. J Am Vet Med Assoc 1998; 212:681–684.

    • Search Google Scholar
    • Export Citation
  • 22.

    Stokol T, Blue JT, French TW. Idiopathic pure red cell aplasia and nonregenerative immune-mediated anemia in dogs: 43 cases (1988–1999). J Am Vet Med Assoc 2000; 216:1429–1436.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Aldridge A, Neims AH. The effects of phenobarbital and β-naphthoflavone on the elimination kinetics and metabolite pattern of caffeine in the Beagle dog. Drug Metab Dis 1979; 7:378–382.

    • Search Google Scholar
    • Export Citation
  • 24.

    Bekersky I, Maggio AC, Mattaliano V Jr, et al. Influence of phenobarbital on the disposition of clonazepam and antipyrine in the dog. J Pharmacokinet Biopharm 1977; 5:507–512.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Sams RA, Muir WW. Effects of phenobarbital on thiopental pharmacokinetics in Greyhounds. Am J Vet Res 1988; 49:245–249.

  • 26.

    Ciaccio PJ, Halpert JR. Characterization of a phenobarbital-inducible dog liver cytochrome P450 structurally related to rat and human enzymes of the P450IIIA (steroid-inducible) gene subfamily. Arch Biochem Biophys 1989; 271:284–299.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Nossaman BC, Amouzadeh HR, Sangiah S. Effects of chloramphenicol, cimetidine and phenobarbital on and tolerance to xylazine-ketamine anesthesia in dogs. Vet Hum Toxicol 1990; 32:216–219.

    • Search Google Scholar
    • Export Citation
  • 28.

    Kantrowitz LB, Peterson ME, Trepanier LA, et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in epileptic dogs treated with anticonvulsants. J Am Vet Med Assoc 1999; 214:1804–1808.

    • Search Google Scholar
    • Export Citation
  • 29.

    Hojo T, Ohno R, Shimoda M, et al. Enzyme and plasma protein induction by multiple oral administrations of phenobarbital at a therapeutic dosage regimen in dogs. J Vet Pharmacol Ther 2002; 25:121–127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Orito K, Saito M, Fukunaga K, et al. Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs. J Vet Pharmacol Ther 2008; 31:259–264.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Gieger TL, Hosgood G, Taboada J, et al. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. J Vet Intern Med 2000; 14:277–281.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Muller PB, Wolfsheimer KJ, Taboada J, et al. Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. J Vet Intern Med 2000; 15:157–164.

    • Search Google Scholar
    • Export Citation
  • 33.

    Trepanier LA, Babish JG. Effect of dietary chloride content on the elimination of bromide by dogs. Res Vet Sci 1995; 58:252–255.

  • 34.

    Shaw N, Trepanier LA, Center SA, et al. High dietary chloride content associated with loss of therapeutic serum bromide concentrations in an epileptic dog. J Am Vet Med Assoc 1996; 208:234–236.

    • Search Google Scholar
    • Export Citation
  • 35.

    Nichols ES, Trepanier LA, Linn K. Bromide toxicosis secondary to renal insufficiency in an epileptic dog. J Am Vet Med Assoc 1996; 208:231–233.

    • Search Google Scholar
    • Export Citation
  • 36.

    Rossmeisl JH, Inzana KD. Clinical signs, risk factors, and outcomes associated with bromide toxicosis (bromism) in dogs with idiopathic epilepsy. J Am Vet Med Assoc 2009; 234:1425–1431.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Extralabel drug use in animals; final rule, 21 CFR Part 530. Fed Regist 1996; 61:57731–57746.

  • 38.

    US FDA Center for Veterinary Medicine. Chapter 6, Subchapter 600, Sec. 608.400—compounding of drugs for use in animals, July 2003. In: Compliance policy guide: compliance policy guidance for FDA staff and industry. Rockville, Md: US FDA, 2003. Available at: www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm074656.htm. Accessed Mar 27, 2012.

    • Search Google Scholar
    • Export Citation
  • 39.

    Boothe DM. Therapeutic drug monitoring. In: Boothe DM, ed. Small animal clinical pharmacology and therapeutics. Philadelphia: WB Saunders Co, 2001;60–72.

    • Search Google Scholar
    • Export Citation
  • 40.

    Bauer LH. Handbook of clinical pharmacokinetics. Columbus, Ohio: McGraw-Hill, 2005.

  • 41.

    US FDA Good Clinical Practice Program Office of Science & Health Coordination, Office of the Commissioner. Guidance for sponsors, clinical investigators, and IRBs: data retention when subjects withdraw from FDA-regulated clinical trials. HF-34. Available at: www.fda.gov/oc/gcp/draft.html. Accessed Jun 22, 2010.

    • Search Google Scholar
    • Export Citation
  • 42.

    Loomis KF, Frye RM. Evaluation of the Abbott TDx for the stat measurement of phenobarbital, phenytoin, carbamazepine, and theophylline. Am J Clin Pathol 1983; 80:686–691.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Sunshine I. Bromide. Type A. Procedure. In: Sunshine I, ed. CRC methodology for analytical toxicology. Cleveland: CRC Press, 1975;54–55.

    • Search Google Scholar
    • Export Citation
  • 44.

    US Pharmacopeia (USP-NF). USP33-NF28. Potassium bromide oral solution monograph. In: The United States pharmacopeia. Rockville, Md: US Pharmacopeial Convention, 2010;3:4375.

    • Search Google Scholar
    • Export Citation
  • 45.

    Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006; 354:731–739.

  • 46.

    Lam FC, Hung CT, Perrier DG. Estimation of variance for harmonic mean half-lives. J Pharm Sci 1985; 74:229–231.

  • 47.

    Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol 2005; 33:227–234.

  • 48.

    Kluger EK, Malik R, Ilkin WJ, et al. Serum triglyceride concentration in dogs with epilepsy treated with phenobarbital or with phenobarbital and bromide. J Am Vet Med Assoc 2008; 233:1270–1277.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49.

    Gaskill CL, Cribb AE. Pancreatitis associated with potassium bromide/phenobarbital combination therapy in epileptic dogs. Can Vet J 2000; 41:555–558.

    • Search Google Scholar
    • Export Citation
  • 50.

    Steiner JM, Xenoulis PG, Anderson JA, et al. Serum pancreatic lipase immunoreactivity concentrations in dogs treated with potassium bromide and/or phenobarbital. Vet Ther 2008; 9:37–44.

    • Search Google Scholar
    • Export Citation

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