Benzodiazepines, or benzos, are a class of medication prescribed for the short-term management of anxiety, insomnia, seizures, and muscle spasms. While commonly prescribed, benzos come with some risks – including the potential for misuse, addiction, and fatal overdose.
Fortunately, there is an antidote for benzodiazepine overdose or benzodiazepine toxicity: Flumazenil. Though this antidote can treat and potentially reverse a benzo overdose, it’s not without risks of its own.
Benzodiazepines are central nervous system (CNS) depressant medications, or sedative hypnotics, that are used to calm an overexcited nervous system and treat the symptoms of anxiety, sleep problems, muscle spasms, and seizures.
Some of the commonly prescribed benzos include Ativan (lorazepam), Xanax (alprazolam), Valium (diazepam), and Klonopin (clonazepam).[1] These drugs may work differently, but they belong to the same class and have similar effects and risks.
Though benzos are commonly used to treat legitimate medical conditions, they’re also a drug that’s misused for non-medical purposes. People may misuse benzos to get high, to increase the euphoria they get from other drugs like opioids or alcohol, or to relieve withdrawal symptoms from stimulants like cocaine.
Benzodiazepine overdoses are somewhat rare on their own. Usually, severe toxicity or fatal overdoses are more likely to happen if you use benzodiazepines with other substances, especially other CNS depressants like opioids or alcohol.[2]
The number of overdose deaths involving benzodiazepines and opioids – particularly fentanyl – increased significantly between 1999 and 2017.[3] The number of overdoses decreased from 2017 to 2020, but it increased again after 2020. Of the overdose deaths that involved benzos, 92.7% also involved opioids.[4]
If you take a larger dose of benzos than your body can handle, overdose occurs. The signs of a benzodiazepine overdose may include:[5]
The risk of benzodiazepine toxicity and its severity are increased by the type of benzodiazepine, the dosage, and the use of other substances – particularly sedatives, alcohol, or opioids. Alprazolam, which is sold under the brand name Xanax, has been associated with higher toxicity in overdoses compared to some other benzodiazepines.[6]
If you suspect someone is overdosing on benzodiazepines or experiencing a mixed overdose, call 911 immediately. Tell the medical team about suspected benzodiazepine intoxication, what types of substances are involved, and the amounts if you know. Stay with the person until help arrives. If they stop breathing or cardiac arrest occurs, perform mouth-to-mouth resuscitation and cardiopulmonary resuscitation (CPR) if you’re trained.
Many people are familiar with naloxone, an opioid antagonist that can be used to reverse an opioid overdose. An antidote exists for benzodiazepine poisoning as well, flumazenil, which may cause a complete or partial reversal of the effects of a benzodiazepine overdose.[7]
Flumazenil treatment is given as an infusion into a vein. A healthcare provider often does this to ensure your vital signs are monitored after use, including your breathing, blood pressure, and other vital signs, and to provide supportive care.[8]
The use of flumazenil may not completely remedy the depressed breathing that occurs with a benzo overdose because it’s a short-acting medication with a short half-life. It may need to be given in multiple doses every 20 minutes to prevent dangerous complications from respiratory depression.
Though flumazenil is generally safe and effective, it can have side effects and risks. The common side effects of flumazenil include:[9]
Most of these side effects are preferable to the effects of a benzo overdose. However, serious side effects can occur, including:[10]
In some cases, flumazenil may have an increased risk of seizures, especially in people who have sedative addiction withdrawal symptoms.[11] Fatal seizures may also occur in people who have recently received injectable benzodiazepines or people who have had symptoms of a seizure before receiving flumazenil.
Flumazenil should not be given after taking large doses of certain tricyclic antidepressant drugs because dangerous or life-threatening side effects can occur. These tricyclic antidepressants include amitriptyline, doxepin, clomipramine, desipramine, imipramine, or nortriptyline.[12]
Unlike naloxone, flumazenil is not considered an antidote that can be given by anyone other than medical professionals with the appropriate training. After flumazenil, the person needs to be carefully monitored for any adverse events or severe respiratory depression.
Benzodiazepine overdose is possible if you take too much of a drug. However, the risk is much higher if you’re misusing benzodiazepines at high doses or mixing them with other drugs. There’s also a higher risk of becoming addicted to benzodiazepines or multiple substances, which is a substance use disorder.
An addiction to benzodiazepines, benzodiazepine-like drugs, or other sedative-hypnotics like barbiturates is a sedative, hypnotic, or anxiolytic use disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The criteria for this disorder include:[13]
Benzodiazepine misuse and addiction can be difficult to overcome, but it is possible with treatment. If you’re addicted to benzos or have been misusing them, especially with other drugs, you mustn’t try to quit cold turkey on your own. Stopping benzos after prolonged use or dramatically reducing your dosage can lead to unpleasant withdrawal symptoms because of benzodiazepine dependence, some of which can be life-threatening.
Stopping benzos requires a taper schedule to wean you off the drug and reduce the severity of withdrawal symptoms from benzodiazepine dependence, which a doctor should handle. If you’re addicted to benzos or use other substances, medical detox may be the best choice. This setting provides a medical team to manage withdrawal symptoms, monitor your health, and keep you as safe and comfortable as possible while the drugs clear your system.
Detox is an important step for severe withdrawal, but it’s not enough to treat addiction on its own. A comprehensive addiction treatment plan is necessary to identify the thought patterns, emotions, and social behaviors that contribute to addiction. Inpatient and outpatient programs offer personalized treatment for Benzo addiction that may include behavioral therapies, individual and group counseling, and peer support groups.
Flumazenil is a helpful drug to help treat or reverse a benzodiazepine overdose and buy time for medical treatment, but it’s not a guarantee. There are risks with flumazenil administration as a treatment of benzodiazepine overdose as well, including possible seizures and adverse effects. If you’re struggling with benzodiazepine misuse or addiction, it’s important to get help as soon as possible to avoid the risk of overdose and get on a healthier path.
Flumazenil is an antidote for benzodiazepine (BZD) toxicity. It’s a competitive antagonist of the benzodiazepine receptors that the drugs act on and can reverse the sedative effects of BZD overdose, including sedation and respiratory depression, but it has risks of its own.[14]
Flumazenil is a benzodiazepine antagonist that’s used in benzo overdose emergencies. It’s also used to reverse benzodiazepine-induced sedation after surgery.
Flumazenil is controversial for some healthcare professionals because there is a risk of the drug causing acute benzodiazepine withdrawal and seizures when it’s used in the case of a benzo overdose. Like any drug, healthcare professionals must weigh the benefits against the risks of flumazenil.
[1] (2024, May 17). Benzodiazepines: What they are, uses, Side Effects & Risks. Cleveland Clinic. Retrieved from https://my.clevelandclinic.org/health/treatments/24570-benzodiazepines-benzos
[2] Trends in nonfatal and fatal overdoses involving … – cdc. (n.d.). Retrieved from https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7034a2-H.pdf
[3] U.S. Department of Health and Human Services. (2024, September 30). Drug overdose deaths: Facts and figures. National Institutes of Health. Retrieved from https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
[4] Trends in nonfatal and fatal overdoses involving … – cdc. (n.d.). Retrieved from https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7034a2-H.pdf
[5] Kang, M. (2023, June 26). Benzodiazepine toxicity. StatPearls [Internet]. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK482238/
[6] Isbister, G. K., O’Regan, L., Sibbritt, D., & Whyte, I. M. (2004). Alprazolam is relatively more toxic than other benzodiazepines in overdose. British Journal of Clinical Pharmacology, 58(1), 88–95. https://doi.org/10.1111/j.1365-2125.2004.02089.x
[7,8,9,10,11,12] Flumazenil uses, Side Effects & Warnings. Drugs.com. (n.d.). Retrieved from https://www.drugs.com/mtm/flumazenil.html
[13] Sedative, hypnotic, or anxiolytic (benzodiazepine) use disorder. PsychDB. (2024, May 9). Retrieved from https://www.psychdb.com/addictions/sedative-hypnotics/1-use-disorder
[14] TJ;, K. (n.d.). Flumazenil: An antidote for benzodiazepine toxicity. American family physician. Retrieved from https://pubmed.ncbi.nlm.nih.gov/8438687/
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