Is the use of flumazenil in suspected benzodiazepine overdose associated with increased likelihood of seizures?
Date First Published:
August 27, 2026
Last Updated:
August 27, 2026
Report by:
Gregory Yates, Doctor (Manchester University Foundation Trust)
Search checked by:
Jimena Prieto, Doctor
Three-Part Question:
In [adult ED patients with suspected benzodiazepine overdose] is [flumazenil] associated with [increased risk of seizures?]
Clinical Scenario:
An unknown 24-year-old patient is brought to the emergency department (ED) by ambulance after having been found unresponsive in a hotel room. They are hypotensive, unresponsive, and breathing very slowly. The paramedics inform you that empty medication packets were found on the scene, including diazepam. As you prepare equipment for emergency intubation, one of your team suggests a trial of flumazenil. You are worried that it could cause a seizure – but is there is evidence for this?
Search Strategy:
EMBASE and MEDLINE databases (1946-2026) were searched utilising the Ovid interface and the following strategy utilising keywords and Medical Subject Headings:
1 flumazenil.mp.
2 exp flumazenil/
3 emergency department.mp.
4 exp emergency department/
5 exp emergency care/
6 1 or 2
7 3 or 4 or 5
8 6 and 7
9 remove duplicates from 8
1 flumazenil.mp.
2 exp flumazenil/
3 emergency department.mp.
4 exp emergency department/
5 exp emergency care/
6 1 or 2
7 3 or 4 or 5
8 6 and 7
9 remove duplicates from 8
Search Details:
Case reports, conference abstracts, review articles, and non-English language papers were removed.
The Google Scholar ‘cited by’ function was then used to find studies that had referenced the papers we identified as relevant in our database searches. Finally, the reference lists of relevant papers were screened for studies missed by our search process.
The Google Scholar ‘cited by’ function was then used to find studies that had referenced the papers we identified as relevant in our database searches. Finally, the reference lists of relevant papers were screened for studies missed by our search process.
Outcome:
260 papers were identified using our search strategy. 249 were excluded on abstract review as they were not relevant to the three-part question outlined above.
Eleven studies underwent full text review. Four were removed because they excluded patients with multi-drug overdose, pro-convulsant use, and/or a known history of seizures. One was removed because adverse events were not reported.
Six papers [1-6] were retained for final analysis: four retrospective observational studies and two randomised trials. Three authors were contacted [1-3] to provide additional data (including qualitative information on seizure events) and one [1] did so.
Eleven studies underwent full text review. Four were removed because they excluded patients with multi-drug overdose, pro-convulsant use, and/or a known history of seizures. One was removed because adverse events were not reported.
Six papers [1-6] were retained for final analysis: four retrospective observational studies and two randomised trials. Three authors were contacted [1-3] to provide additional data (including qualitative information on seizure events) and one [1] did so.
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|
Author Commentary:
Our key results are summarised in Table 1. In a pooled sample of 2,029 suspected benzodiazepine overdoses, seizures occurred in only twenty (<1%) cases. Qualitative information was generally unavailable [4-6] but in two patients, seizures had occurred prior to flumazenil administration.
The quality of evidence in this review was mixed. Most studies were observational, involving patients who were deemed “suitable” for flumazenil by their doctors. Higher-risk cases may have been avoided, and adverse events under-reported. It is debatable whether this occurred in practice, given the inclusion of nearly eight-hundred patients with multi-drug poisoning and minimal information about prior seizures.
The alternative to flumazenil in critically intoxicated patients is intubation. A recent multi-centre trial [7] showed worsened outcomes with intubation in acute poisoning, including greater incidence of pneumonia. We would contend that in severe benzodiazepine overdoses, flumazenil is likely to present fewer risks than intubation. A sensible approach would be to trial flumazenil once airway equipment and personnel are assembled, so that the team is ready to intubate if there is ongoing coma or a seizure.
The quality of evidence in this review was mixed. Most studies were observational, involving patients who were deemed “suitable” for flumazenil by their doctors. Higher-risk cases may have been avoided, and adverse events under-reported. It is debatable whether this occurred in practice, given the inclusion of nearly eight-hundred patients with multi-drug poisoning and minimal information about prior seizures.
The alternative to flumazenil in critically intoxicated patients is intubation. A recent multi-centre trial [7] showed worsened outcomes with intubation in acute poisoning, including greater incidence of pneumonia. We would contend that in severe benzodiazepine overdoses, flumazenil is likely to present fewer risks than intubation. A sensible approach would be to trial flumazenil once airway equipment and personnel are assembled, so that the team is ready to intubate if there is ongoing coma or a seizure.
Bottom Line:
Flumazenil has a lower risk of seizures than has previously been described and in severe benzodiazepine overdoses, emergency intubation is likely to present a greater risk.
Level of Evidence:
Level 1: Recent well-done systematic review was considered or a study of high quality is available
References:
- . [1] Ramos JR, Peláez MG, Clemente YC, Requejo CC, Alcón EV, Mora JR, Blanch CT, Palomares AG, Costas DG, FLUMA-URG working group. Adverse events associated with the use of flumazenil in the Emergency Department. Medicina Clínica (English Edition). 2026 Feb 5:107312.
- . [2] Segev O, Yelak A, Scolnik D, Rimon A, Glatstein MM. Flumazenil in the Treatment of Benzodiazepine Toxicity: The Experience of a Large Urban Tertiary Care. ISRAEL MEDICAL ASSOCIATION JOURNAL. 2026 Jan 1;28(1):40-4.
- . [3] Kim J, Kim SH, Choi SP, Zhu JH, Kim SW, Kwon MK, Oh JH. Continuous Flumazenil Infusion and Time to Consciousness Recovery in Benzodiazepine Poisoning: A Retrospective Cohort Study. Journal of Clinical Medicine. 2025 Aug 24;14(17):5983.
- . [4] Vohra V, Darling A, Welch R, Daviskiba S, King AM. Low risk of adverse events associated with flumazenil administration: a retrospective poison center analysis of acutely poisoned patients. Clinical Toxicology. 2025 Aug 3;63(8):593-602.
- . [5] Spivey WH, Roberts JR, Derlet RW. A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. Annals of emergency medicine. 1993 Dec 1;22(12):1813-21.
- . [6] Bayer MJ, Danzl D, Gay GR, Gibler B, Jackimczyk K, Kent T, Kulig K, Leikin JB, Litovitz T, Overton D, Paul K. Treatment of benzodiazepine overdose with flumazenil. Clinical therapeutics. 1992;14(6).
- . [7] Freund Y, Viglino D, Cachanado M, Cassard C, Montassier E, Douay B, Guenezan J, Le Borgne P, Yordanov Y, Severin A, Roussel M. Effect of noninvasive airway management of comatose patients with acute poisoning: a randomized clinical trial. Jama. 2023 Dec 19;330(23):2267-74.