Flumazenil is a recently discovered pharmacologic antagonist of the CNS effects 
of benzodiazepines. It acts by binding CNS benzodiazepine receptors and 
competitively blocking benzodiazepine activation of inhibitory GABAergic 
synapses. Animal studies and some human studies appear to demonstrate that 
flumazenil has weak intrinsic agonist activity; on the other hand, studies are 
inconclusive in demonstrating any inverse agonist effects of this agent. 
Evidence available suggests that flumazenil is well tolerated in human beings 
over a broad range of doses when given either orally or parenterally and does 
not produce serious adverse effects. In the setting of isolated benzodiazepine 
overdose, flumazenil is capable of completely reversing coma within one to two 
minutes, with this effect lasting between one and five hours. Repeat doses can 
be given safely to reverse recurrent effects of longer-acting benzodiazepines. 
Flumazenil is undergoing further evaluation by the Food and Drug Administration; 
should this drug receive approval, it is likely to be used in emergency 
departments as well as in a variety of other clinical settings. First, it could 
be used to effect rapid reversal of benzodiazepine-induced sedation that has 
been administered to facilitate medical, orthopedic, and surgical procedures, 
particularly in the event of inadvertent respiratory depression. Second, 
flumazenil might have a therapeutic role in the management of patients who have 
taken benzodiazepine overdoses. Although most of these patients can be managed 
successfully with supportive therapy alone, it is possible that the use of 
flumazenil may obviate the need for intubation and respiratory support in such 
patients and eliminate the possible adverse effects of even short-term 
endotracheal intubation. Finally, flumazenil could have both diagnostic and 
therapeutic value in patients with acute alterations of mental status of unknown 
etiology, particularly when possible drug overdose is a consideration. Because 
flumazenil appears to be specific in its antagonism of benzodiazepine-induced 
respiratory and CNS depression, it could be used empirically to confirm or 
exclude a role of benzodiazepines in the generation of mental status changes in 
the setting of overdose or coma of unknown origin. This in turn might obviate 
the need for further expensive (eg, computed tomography) and sometimes invasive 
(eg, lumbar puncture) diagnostic modalities. This might be particularly useful 
because there is nothing about benzodiazepine-induced coma that clearly 
distinguishes it from other causes of coma; thus, there are no signs or symptoms 
that may reasonably allow benzodiazepine overdose to be confirmed or eliminated 
on clinical grounds. Further studies will continue to define the ultimate use of 
this new agent.