Midazolam is a benzodiazepine that induces sedation and anesthesia. It is commonly used to reduce anxiety before an operation and as an induction agent of general anesthesia. It can also help in the management of acute seizures.1 According to one estimate, midazolam is used in approximately 75% of routine sedations in the United States.2 Midazolam induces its sedative effects by binding to receptors that normally bind the neurotransmitter GABA, thereby increasing the activity of GABA. In turn, it promotes a greater frequency of neuronal chloride channel opening, causing the hyperpolarization of nerve cells and the inhibition of nervous signals.1 However, there are rare instances when midazolam produces a paradoxical agitation—an effect opposite of its intended result.
In less than 1% of patients, midazolam can lead to a paradoxical increase in agitation, excitement, restlessness, aggression, and spasms, rather than the intended sedative effect. The effects usually manifest within 5 minutes of midazolam administration and generally do not resolve quickly on their own. This reaction is not unique to midazolam: paradoxical effects can occur in response to many benzodiazepines, including barbiturates and volatile anesthetics.3
The exact mechanism responsible for paradoxical agitation is unclear, though several possibilities have been suggested. One posits that midazolam, as a benzodiazepine, can impair the brain’s ability to inhibit certain instinctive or emotional responses—known as a loss of cortical restraint—similar to the effects alcohol may exert on a person.4 Alternatively, benzodiazepines are known to reduce the transmission of serotonin, a neurotransmitter involved in a wide range of bodily functions and processes, including mood and cognition. Lower concentrations of serotonin could therefore lead to agitated behavior.5
Many case reports of paradoxical agitation with midazolam describe reversing the effects with flumazenil, a GABA receptor antagonist often used in overdose emergencies. Administering additional midazolam does not work and only delays the time to a patient regaining awareness.4 Though less commonly used in clinical practice, ketamine has also been shown to reverse midazolam-induced agitation. In one randomized controlled trial, children undergoing surgery who developed a paradoxical reaction were given either extra midazolam, ketamine, or a placebo. 3.4% of the participants experienced agitation, and those who received ketamine responded rapidly, while those in the other two groups had poor responses and eventually required a rescue dose of ketamine.6
Similar to the uncertainty surrounding the mechanism of paradoxical agitation, it is also unclear which patients are at greater risk for experiencing it. Reported risk factors include younger age, alcohol abuse, and genetic background.7 Genetic variations in the benzodiazepine receptors of GABA, for instance, can lead to different reactions.
Given the ubiquity of midazolam, gaining more clarity on the mechanisms and nature of midazolam-induced paradoxical agitation is of great importance in ensuring optimal patient outcomes. According to one anesthesiologist, paradoxical reactions have historically not received the attention they deserve in the anesthesia community “because they do not greatly affect the vital signs and are often not recalled due to the amnesia-producing properties of the drug itself”5—emphasizing the importance of further research in this area.
References
- Lingamchetty, T. N., Hosseini, S. A. & Saadabadi, A. Midazolam. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
- Sivakumar, S., Mendonca, R., Demeterio, D. & Girshin, M. Paradoxical Reactions to Midazolam in a Term Parturient After Intravenous Sedation During Cesarean Section. Cureus 13, e17678 (2021), DOI: 10.7759/cureus.17678
- Cabrera, L. S., Santana, A. S., Robaina, P. E. & Palacios, M. S. Paradoxical reaction to midazolam reversed with flumazenil. J Emerg Trauma Shock 3, 307 (2010), DOI:10.4103/0974-2700.66551
- Mancuso, C. E., Tanzi, M. G. & Gabay, M. Paradoxical reactions to benzodiazepines: literature review and treatment options. Pharmacotherapy 24, 1177–1185 (2004), DOI: 10.1592/phco.24.13.1177.38089
- Moon, Y. E. Paradoxical reaction to midazolam in children. Korean J Anesthesiol 65, 2–3 (2013), DOI: 10.4097/kjae.2013.65.1.2
- Golparvar, M., Saghaei, M., Sajedi, P. & Razavi, S. S. Paradoxical reaction following intravenous midazolam premedication in pediatric patients – a randomized placebo controlled trial of ketamine for rapid tranquilization. Paediatr Anaesth 14, 924–930 (2004), DOI: 10.1111/j.1460-9592.2004.01349.x
- Park, S., Ibrahim, M. & Torres, A. Persistent Paradoxical Reaction to Midazolam despite General Anesthesia with Dexmedetomidine. Case Rep Anesthesiol 2024, 4152422 (2024), DOI: 10.1155/2024/4152422
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