1. Aschenbrenner, Diane S. MS, RN


* The boxed warning for drugs in the benzodiazepine class has been strengthened to further emphasize the risk of overdose and death, especially if combined with opioids, alcohol, or illicit drugs, and the risk of abuse, misuse, addiction, physical dependence, and withdrawal.



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Benzodiazepines were first approved in the early 1960s and became a popular prescription treatment for insomnia and anxiety (see How Do Benzodiazepines Work?). They were much less likely to cause a fatal overdose than earlier barbiturates. Since their introduction, dozens of different benzodiazepines have been created and marketed. Their uses include treatment of anxiety, seizures, insomnia, agitation, withdrawal states, and procedural sedation. However, benzodiazepines have always carried an additional risk of respiratory depression when combined with other central nervous system (CNS) depressants. They have also long been known to have an associated risk of addiction and abuse.


According to the Food and Drug Administration (FDA), an estimated 92 million benzodiazepine prescriptions were dispensed from outpatient pharmacies in the United States in 2019; the three most commonly prescribed drugs being alprazolam, clonazepam, and lorazepam. In 2016, a boxed warning stating the risk of combining opioids and benzodiazepines was included in the benzodiazepines' labeling. Now, the FDA has announced a new, stronger revision to the warning to further emphasize the risk of overdose and deaths from benzodiazepines, especially if combined with opioids, alcohol, or illicit drugs. The boxed warning will also highlight the risk of abuse, misuse, addiction, physical dependence, and withdrawal. In addition, other sections of the labeling will be revised, including warnings and precautions, drug abuse and dependence, and patient counseling information. The language in the patient medication guide will also be strengthened.

Box 1 - Click to enlarge in new windowBox 1. How Do Benzodiazepines Work?

The FDA based the decision to revise the boxed warning on its review of postmarketing databases and the literature exploring benzodiazepine use, abuse, misuse, addiction, and physical dependence. Its conclusion was that abuse and misuse were common and contributed to an increase in overdose deaths, although most of the harm occurred when a benzodiazepine was used in conjunction with other drugs. The FDA states that an estimated 5.4 million Americans age 12 years or older abused or misused a benzodiazepine in 2017. An overdose of a benzodiazepine alone is rarely lethal as little respiratory depression occurs despite evidence of other CNS depression. The most common symptoms of toxicity include slurred speech, ataxia, and altered mental status. However, when a benzodiazepine is taken in large doses with other CNS depressants, most commonly alcohol, there is a risk of serious respiratory depression. These patients may present to the ED in a stuporous or comatose state and need immediate airway management.


The FDA evaluated its Adverse Event Reporting System database of 104 cases that solely involved benzodiazepine use; during this evaluation, the agency identified dependence and withdrawal symptoms even when the drug was prescribed for therapeutic use. Dependence onset varies, with some patients reporting it as soon as a few weeks after starting the drug. Withdrawal is more likely if the drug is stopped suddenly rather than tapered. Benzodiazepine withdrawal symptoms include CNS effects (insomnia, increased anxiety, panic attacks, memory impairment, depression, muscle tension, muscle spasms, blurred vision, seizures, trouble concentrating, clouded thinking, mood swings, agitation, muscle twitching, and loss of appetite), cardiac effects (rate and rhythm changes), and gastrointestinal effects (nausea, diarrhea, and abdominal pain). Severe withdrawal symptoms include catatonia, seizures, delirium tremens, depression, hallucinations, suicidal or homicidal thoughts, mania, and psychosis. Protracted withdrawal symptoms can last up to a year.


Nurses who work with patients prescribed a benzodiazepine should advise them to avoid drinking alcohol because this increases the risk of respiratory and other CNS depression, and can be a lethal combination. Patient education should also include information on dependence and withdrawal. Dependence does not mean addiction. Rather, it means that the body has become accustomed to a substance and reacts if the substance is suddenly stopped (withdrawn). Patients should be told not to suddenly stop taking the prescribed benzodiazepine. Nurses should also teach patients to take the benzodiazepine as prescribed, because misuse (such as taking more than the required dose) or abuse (taking the drug to produce a high) increases the risk of overdose and death. Benzodiazepines need to be kept locked away from children to prevent unintentional overdose.


NPs who prescribe benzodiazepines should use a standardized screening tool to assess the patient's risk of abuse, misuse, and addiction prior to prescribing. Precaution is urged when prescribing both a benzodiazepine and an opioid. Benzodiazepines should be prescribed for as short a time as possible. Clinicians should take care not to prescribe long term those products recommended solely for short-term use. Benzodiazepines for short-term use include diazepam injection (Valium), nasal spray (Valtoco), and rectal gel (Diastat); midazolam injection (Seizalam) and nasal spray (Nayzilam), and lorazepam injection (Ativan).


When stopping a benzodiazepine, patients should taper the drug slowly. Although there is no standard tapering schedule, a slow approach of weeks to months is recommended. Temporarily stopping the taper may be necessary if the patient experiences significant withdrawal symptoms. Patients should be monitored closely for the severe or life-threatening withdrawal symptoms noted above.


If a patient experiences an adverse effect from a benzodiazepine, it should be reported to the FDA MedWatch program:


To read the FDA Drug Safety Communication on benzodiazepines, go to