Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures

N Engl J Med. 1985 Jul 18;313(3):145-51. doi: 10.1056/NEJM198507183130303.


We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Carbamazepine / adverse effects
  • Carbamazepine / therapeutic use*
  • Clinical Trials as Topic
  • Double-Blind Method
  • Epilepsies, Partial / drug therapy
  • Epilepsy / drug therapy*
  • Erectile Dysfunction / chemically induced
  • Female
  • Follow-Up Studies
  • Humans
  • Leukocyte Count
  • Lupus Vulgaris / chemically induced
  • Lymphoma / chemically induced
  • Male
  • Middle Aged
  • Phenobarbital / adverse effects
  • Phenobarbital / therapeutic use*
  • Phenytoin / adverse effects
  • Phenytoin / therapeutic use*
  • Primidone / adverse effects
  • Primidone / therapeutic use*
  • Psychoses, Substance-Induced / etiology


  • Primidone
  • Carbamazepine
  • Phenytoin
  • Phenobarbital