FLUMAZENIL INDUCES SEIZURES AND DEATH IN MIXED COCAINE-DIAZEPAM INTOXICATIONS

Study hypothesis: Administration of the benzodiazepine antagonist flum azenil may unmask seizures in mixed cocaine-benzodiazepine intoxicatio n. Design: Male Sprague-Dawley rats received 100 mg/kg cocaine IP alon e, 5 mg/kg diazepam alone, or a combination of diazepam and cocaine. T hree minutes later, groups were challenged with vehicle or flumazenil 5 or 10 mg/kg IP. Animal behavior, seizures (time to and incidence), d eath (time to and incidence), and cortical EEG tracings were recorded. Interventions: Administration of flumazenil to animals after they had received a combination dose of cocaine and diazepam. Results: In grou p 1, animals received cocaine followed by vehicle. This resulted in 10 0% developing seizures and death. Group 2 received diazepam alone foll owed by vehicle. Animals became somnolent and none died. Group 3 recei ved diazepam followed by 5 mg/kg flumazenil. Animals became somnolent after diazepam and then active after flumazenil administration. In gro up 4, a combination of cocaine and diazepam was administered simultane ously. This resulted in no overt or EEG-detectable seizures and a 50% incidence of death. Group 5 received a similar combination of cocaine and diazepam, followed later by 5 mg/kg flumazenil. This resulted in a n increased incidence of seizures, 90% (P<.01), and death, 100% (P les s-than-or-equal-to .01), compared with group 4. Group 6 received cocai ne and diazepam followed by 10 mg/kg flumazenil. This also resulted in an increased incidence of seizures, 90% (P less-than-or-equal-to .01) , and death, 90% (P less-than-or-equal-to .05), compared with group 4. Conclusion: Flumazenil can unmask seizures and increase the incidence of death in a model of combined cocaine-diazepam intoxications.