FlumazeNOW!

Author: Justin Corcoran MD

Internal Reviewer: Annie Arens MD

In order to understand flumazenil, it’s important to understand how GABA works. First, there are two primary types of GABA receptors; the one we care most about is the GABA-A receptor:

This is a GABA sensitive chloride channel. When two molecules of GABA bind the receptor, the channel opens, chloride conductance increases, and the cell membrane is hyperpolarized. This hyperpolarization makes it more difficult for the neuron to reach threshold, and thus makes it LESS likely to fire an action potential.

The GABA-A receptor has a bunch of binding sites for different toxins; while its not important to know each individual site, it is important to know a few things:

1. Benzodiazepines have their own binding site (that is shared with the sleep-inducing “Z” drugs like zolpidem, zaleplon, etc.)
2. Benzodiazepine binding increases the opening frequency of the channel in response to GABA, but cannot open the channel without GABA present, as opposed to barbiturates, which, at high enough concentrations, can open the channel directly.
3. Other drugs, such as ethanol, work remotely from the benzodiazepine binding site

Enter flumazenil. Flumazenil is a competitive inhibitor of the benzodiazepine binding site on the GABA-A receptor. As such, it can be used clinically for reversal of sedative hypnotic toxidrome that is produced by benzodiazepines (and may be helpful with the aforementioned “Z” drugs as well).

Picture it…the Emergency Department…Imagine you are seeing a 55 year old male who presents to with a chief complaint of depressed mental status. Vital signs are within normal limits. There is no evidence of traumatic injury. Despite an adequate respiratory rate, the patient continues to obstruct his airway due to underlying obstructive sleep apnea – this improves with jaw thrust.

Would you give flumazenil?

Yes, Flumazenil! The Evidence: :

O Canada! One small double-blind RCT of 41 patients investigated the use of flumazenil for reversal of sedation (GCS < 13) in patients with presumed, unknown, overdose.¹ In an interesting twist, the authors EXCLUDED known benzodiazepine and ethanol ingestions…and tricyclic antidepressants. While flumazenil did not improve hospital costs, it did significantly improve GCS compared to control and no patients had seizures.¹ Not a single one! Concerns have been raised over side effects, with a meta-analysis of RCT data showing an increase in serious adverse events (such as supraventricular tachydysrhythmia, seizures) in the flumazenil group compared to placebo. While there was a risk ratio of 3.81 for giving flumazenil compared to placebo, the absolute event rate was 12/498 in the flumazenil group and 2/492 in the placebo group. Of these events, only 3 were seizures.²

What about flumazenil for benzodiazepines? A retrospective poison center based study (caveat that poison center studies are always somewhat limited) showed that just 13 of 904 (1.4%) patients developed a seizure after flumazenil; of these, 8 had ingested a pro-convulsant drug; 53% of patients had improved mental status following flumazenil.³ One multicenter double-blind placebo controlled RCT evaluated the use of flumazenil to reverse sedation in ED patients with known or suspected benzodiazepine overdoses.³ The authors noted improvement in patients that were subsequently shown to have ingested benzodiazepines, but no improvement in benzodiazepine negative patients (an expected result).⁴

Boo Flumazenil! Controversy:

The primary controversy surrounding flumazenil is that in most cases, we don’t know how frequently they are using benzodiazepines. It’s usually not clear whether this was a one-time thing, or if they use benzodiazepines every day. Chronic benzodiazepine use causes down-regulation of GABA-A receptors, which leads to patients becoming dependent on benzodiazepines. This means that it is uncertain whether flumazenil will cause them to enter an antagonist-induced withdrawal state, and specifically whether it will cause them to seize.

Previous reports of flumazenil induced seizures have frequently occurred in patients in a pro-convulsant state, such as concurrent TCA toxicity.⁵

Suggested algorithm for flumazenil use:

First of all, when should you even consider flumazenil? Many patients with benzodiazepine overdose can simply be observed, since respiratory status typically remains intact with oral benzodiazepine overdose. However, in the case where a patient with a benzodiazepine overdose is thought to imminently need intubation (e.g. they have pooling secretions, are obstructing their airway, or co-ingested another respiratory depressant), then the risks and benefits of flumazenil must be weighed against the risks and benefits of intubation. Dismissing flumazenil out-of-hand is tantamount to considering that there is no risk associated with intubation, which is false.

What if your patient seizes? Remember that flumazenil is a competitive inhibitor of the benzodiazepine receptor site on the GABA-A channel; as such, flumazenil antagonism can be overcome with escalating doses of benzodiazepine. So if the patient does have a seizure, this should prompt higher doses of benzodiazepines and intubation. And, let’s not forget about all the other GABA-potentiating options, like barbiturates and propofol.

Although flumazenil should be considered more frequently in cases of benzodiazepine overdoses, there are a few cases where caution should be used:

• If the patient has an underlying seizure disorder
• If the patient’s expected clinical course is intubation due to other co-ingested drug or other medical process
• If the patient co-ingested a xenobiotic with high seizure risk or where benzodiazepines are expected to be needed therapeutically (e.g. bupropion, citalopram, methamphetamine, bath salts, etc.)

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1. Barnett R, Grace M, Boothe P, et al. Flumazenil in drug overdose: randomized, placebo-controlled study to assess cost effectiveness. Crit Care Med 1999;27(1):78–81.

2. Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication–A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol 2016;118(1):37–44.

3. Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center’s ten-year experience with flumazenil administration to acutely poisoned adults. J Emerg Med 2012;43(4):677–82.

4. Spivey WH, Roberts JR, Derlet RW. A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. Ann Emerg Med 1993;22(12):1813–21.

5. Haverkos GP, DiSalvo RP, Imhoff TE. Fatal seizures after flumazenil administration in a patient with mixed overdose. Ann Pharmacother 1994;28(12):1347–9.