The efficacy of antipyretic agents in prevention of febrile seizures was examined in a randomized, placebo-controlled, double-blind trial at various hospitals in Finland. A total of 231 children who experienced their first febrile seizure, Jan 1, 1997-Dec 31, 2003, were observed for 2 years. Febrile episodes were treated first with rectal diclofenac or placebo. After 8 hours, treatment was continued with oral ibuprofen, acetaminophen, or placebo. Of 851 febrile episodes, 89 (10%) were associated with a febrile seizure. Febrile seizures occurred in 54 (23.4%) of the 231 children. Recurrence rates were not significantly different in the antipyretic and placebo groups: 23.4% (46 of 197) in those treated with antipyretic, and 23.5% (8 of 34) in those receiving placebo (P=0.99). Fever was significantly higher during episodes with seizure vs those without seizure (39.7C vs 38.9C, P<0.001), independent of the medication. Antipyretic agents were ineffective in the prevention of febrile seizure recurrence. All the antipyretics failed to lower the body temperature in children with fever that was associated with febrile seizure recurrence, but they lowered the temperature in episodes not leading to a febrile seizure. Children with recurrences had received extra antipyretic agents more frequently than those without recurrences. 
COMMENT. The ineffectiveness of commonly prescribed antipyretics in the prevention of recurrence of febrile seizures, as demonstrated in this controlled study, is in agreement with the majority of previous randomized trials. Antipyretics may be useful only in improving the general wellbeing of the febrile child. In patients with a prior complex febrile seizure, to prevent recurrence, many pediatric neurologists recommend a combination of antipyretic with diazepam, administered orally at first sign of fever.
While antipyretics failed to prevent or control temperature elevation that resulted in seizure recurrence, they were effective in lowering temperature in episodes unassociated with seizure. The principal aim in therapy is the prevention of an elevation of temperature above the threshold level at which a seizure has previously occurred. Commonly employed antipyretics, while facilitating heat dissipation by increased peripheral blood flow and sweating, have no effect on heat production and temperature elevation. They begin to act when the fever has reached its highest point (Goodman and Gilman, 1955). In laboratory studies of antipyretic agents, aspirin and acetaminophen failed, whereas barbiturates were effective in retarding temperature elevation induced by radiotherm diathermy in animals. High doses of salicylates that cause hyperventilation and respiratory alkalosis lowered the threshold convulsive temperature and exacerbated the hyperthermia-induced seizure . The prevention of febrile seizures by anticonvulsant medications may be as much antipyretic as anticonvulsant effect. Future research in the development of more effective antipyretics should target heat production more than heat dissipation. The authors from Finland comment on the inhibition of different prostaglandins by antipyretics and the potential for different effects on seizure recurrence.