Phenytoin Dependence Syndrome: A Case Report

A 42-year-old man was referred from the Department of Neurology complaining of insomnia and anxiety symptoms for the last 2 months. He was known to have idiopathic generalized tonic clonic seizures and was being treated with tab phenytoin for the last 22 years. He was seizure-free for the last 15 years and experienced gum hypertrophy as a side effect of his drug treatment.

The patient reported that after his last seizure he noticed that whenever he missed his dose of phenytoin for any reason, he would experience craving, restlessness, irritable mood, tremulousness, and inability to sleep. He also reported that as the scheduled time neared for the next dose he would become jittery. These symptoms, except insomnia, would subside on taking the drug in the prescribed dose (i.e., 300 mg). He increased the dose to 400 mg/day which helped him attain a sound sleep. Gradually he increased the dose to 600 mg/day for the same effects, and he maintained on this dose. The patient was cautioned by the treating physician against this dosage increase due to potential adverse effects, but the patient persisted with the use of the drug. When the patient tried to gradually decrease the dose of phenytoin at the rate of 50 mg/day, he was not successful and had a reemergence of craving, insomnia, and dysphoric mood the very next day.

The patient was finally admitted, and we made a working diagnosis of phenytoin-dependence syndrome. He was poorly motivated for therapy and resisted any attempt to taper down the dose of phenytoin. He was prescribed 10 mg/day of zolpidem for his sleep problems, and motivation enhancement sessions were started, but the patient was lost to follow-up.

The patient fulfilled ICD-10 criteria of a possible phenytoin-dependence syndrome. He had a craving for the drug, would have withdrawal symptoms on stopping the drug, and had gradually developed tolerance to the effects, which led to an increase in drug dosage. The patient continued its use despite knowing that the drug led to gum hypertrophy and was not required for controlling his seizures. This is interesting because unlike all other dependence-producing substances, phenytoin is not expected to stimulate the mesolimbic/mesocortical dopaminergic reward circuit. The role of neuroadaptation in neurotransmitters, receptor systems, gene expressions, and of memory and learning need to be further explored with long-term use of antiepileptic drugs.

It can rightly be said that long-term antiepileptic drug therapy carries with it significant morbidity. Therefore, the issue of whether one can withdraw antiepileptic drugs in a patient with epilepsy after a seizure-free interval becomes important in the treatment of vast numbers of patients. This will indeed help us to prevent substituting one symptom complex with another.