Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy

Acta Neurol Scand Suppl. 1983:97:49-67. doi: 10.1111/j.1600-0404.1983.tb01535.x.


Phenobarbital and phenytoin have good antiepileptic effect, but clinically significant untoward effects occur during their long-term use. Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even dementia; these effects are dose related to some extent. Side effects of phenytoin include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis, locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate level, decreased bone mineral content, liver disease, IgA deficiency, gingival hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to the neurotoxic effects of phenytoin are epileptic children with severe brain damage who are on multiple drugs. In those children, balance disturbance may develop and be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic patients, phenytoin intoxication occurred in 73 (56%), of whom 18 experienced persistent loss of locomotion. There is experimental evidence that the toxic action of phenytoin lies at the cellular level, predominantly in the cerebellum. Many experts avoid the long-term use of phenytoin because of its insidious and potentially dangerous side effects.

MeSH terms

  • Abnormalities, Drug-Induced / etiology
  • Brain / drug effects
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Endocrine System Diseases / chemically induced
  • Epilepsy / drug therapy*
  • Female
  • Hematologic Diseases / chemically induced
  • Humans
  • Immunologic Deficiency Syndromes / chemically induced
  • Infant, Newborn
  • Long-Term Care
  • Neurons / drug effects
  • Osteomalacia / chemically induced
  • Peripheral Nerves / drug effects
  • Phenobarbital / adverse effects*
  • Phenobarbital / therapeutic use
  • Phenytoin / adverse effects*
  • Phenytoin / therapeutic use
  • Pregnancy


  • Phenytoin
  • Phenobarbital