Since the 1960s, with the development of chlordiazepoxide (Librium) and shortly thereafter diazepam (Valium), benzodiazepines quickly became mainstream medications secondary to their vastly superior safety profiles when compared to previous sedative-hypnotics such as barbiturates and other non-barbiturates used for the treatment of anxiety and insomnia. Since their initial development, multiple benzodiazepine drugs have been developed over the course of several decades. Benzodiazepines are currently used to treat anxiety, seizures, withdrawal states, insomnia, agitation, and are commonly used for procedural sedation. Due to their many uses and addictive properties, benzodiazepines have been widely prescribed and abused since their development several decades ago. Today, there are over 50 different agents available on the worldwide market and the high incidence of benzodiazepine overdose mirrors their widespread use and availability. 
Leo Sternbach was an Austrian scientist working for Hoffmann-La Roche in Nutley, NJ and has been accredited for his work in developing many drugs, in particular, benzodiazepines. In 1956, he serendipitously created chlordiazepoxide (Librium) which was approved for medical use in 1960. He later developed an improved, safer version named diazepam (Valium) in 1963. Diazepam became widely popular and between 1969 and 1982, it was the most prescribed drug in the United States, with over 2.3 billion doses sold in its peak year in 1978.
While precise data is unavailable, estimates suggest a lifetime prevalence of benzodiazepine use disorder to be less than 1%. Benzodiazepines though are often combined with other drugs. Thus the prevalence of an isolated benzodiazepine use disorder is difficult to determine from epidemiologic studies. Existing data suggest that the lifetime prevalence of tranquilizer and sedative use, which includes benzodiazepines and barbiturates in the United States are around 1% and 1.1% respectively. In 2013, 2% of the United States population (12 years or older) had consumed benzodiazepines or barbiturates for nonmedical use. From 1996 to 2013 benzodiazepine prescriptions increased by 2.5% each year making it one of the most prescribed medications in the world. Substance abuse disorder treatment centers reported admissions for benzodiazepine abuse as the sole primary substance or drug of choice, to have increased by 109% between 2003 and 2013.
Benzodiazepines are organic bases with a benzene ring and a 7-member diazepine moiety, with variable side chains that determine the potency, duration of action, metabolite activity and rate of elimination. Benzodiazepines exert their effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor, which is the primary inhibitory neurotransmitter in the central nervous system. The GABA-A receptor, depending on various arrangements of its subunits determines its affinity for various agents that bind to the receptor. Benzodiazepines bind at the interface of the GABA-A receptor and subsequently locks the receptor into a configuration that increases its affinity for GABA. Benzodiazepines do not alter the production, release or metabolism of GABA but instead potentiates its inhibitory actions by augmenting or enhancing receptor binding. This binding ultimately increases the flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization which decreases the ability to generate an action potential. The low incidence of respiratory depression with benzodiazepines, which differentiates it from barbiturates, is related to the low density of binding sites in the brainstem which houses the respiratory center.
Benzodiazepines taken in toxic doses without other coingestants rarely cause a significant toxidrome. The classic presentation in patients with isolated benzodiazepine overdose will include central nervous system (CNS) depression with normal or near normal vital signs. Many patients will still be arousable and even provide a reliable history. Classic symptoms include slurred speech, ataxia, and altered mental status. Respiratory compromise is uncommon in isolated benzodiazepine ingestions, but if taken with coingestants such as ethanol or other drugs/medications, respiratory depression can be noted. It is important to note that most intentional ingestions of benzodiazepines do involve coingestants, the most common being ethanol, which can lead to substantial respiratory depression and airway compromise. The dose required to produce respiratory compromise is difficult to quantify and depends on multiple factors including dosage, tolerance, weight, age, coingestants, and even genetics. Patients with severe toxicity will present stuporous or comatose, and immediate airway management and mechanical ventilation may be required.
A unique toxidrome related to parenteral (IV/IM) formulations of diazepam (Valium) and lorazepam (Ativan) is propylene glycol poisoning. Propylene glycol is the diluent used in the parenteral formulations for these 2 benzodiazepines, and prolonged use can cause propylene glycol toxicity which includes skin and soft tissue necrosis, hemolysis, cardiac dysrhythmias, hypotension, significant lactic acidosis, seizure, and multisystem organ failure. While propylene glycol toxicity is rare, it must be considered when patients are receiving large or continuous infusions of parenteral benzodiazepines, for example when treating severe sedative or ethanol withdrawal syndromes such as delirium tremens.
Patients with benzodiazepine toxicity will primarily present with CNS depression ranging from mild drowsiness to a coma-like, stuporous state. The classic presentation of an isolated benzodiazepine overdose consists of CNS depression with normal vital signs. Cardiac-related effects and fatalities are rare in pure benzodiazepine toxicities. Respiratory depression or compromise, while less common when compared to barbiturates, is the most important adverse clinical effect requiring immediate intervention. Life-threatening respiratory depression can be seen with large oral ingestions with or without coingestants. Iatrogenic causes of toxicity can be seen when benzodiazepines are combined with other drugs during procedural sedation – in particular with opiates such as fentanyl.
In children with benzodiazepine toxicity, most will have symptoms within 4 hours of ingestion. Ataxia is the most common sign of toxicity in children, occurring in 90% of pediatric patients. Respiratory compromise occurs in less than 10% of pediatric cases, and hypotension has not been reported.
Benzodiazepine overdose is usually suspected or diagnosed based on clinical presentation. Many patients are arousable and can provide supporting information regarding their ingestion. In the acutely poisoned patient that is unable to provide an adequate history, a general approach should be utilized to stabilize the patient.
Before any diagnostic tests are ordered in the patient presenting with altered mental status with suspected overdose or toxicity; any respiratory or abnormal vital signs should be addressed first. Mechanical ventilation may be required to address respiratory compromise and IV fluids administered to address hemodynamic instability.
In terms of general diagnostic testing, routine testing for the acutely poisoned patient should include a point of care glucose to immediately rule out and address hypoglycemia as the cause of altered mental status. Acetaminophen and aspirin levels along with ethanol levels should be ordered to evaluate for possible co-ingestions. An ECG should be ordered to rule out the ingestion of drugs that may widen the QRS or QTc intervals and may precipitate arrhythmias. A pregnancy test should be ordered for all women of childbearing years. A head CT without contrast may be considered to rule out an intracranial abnormality related to the patient presenting acutely altered.
While a standard urine drug screen (UDS) should be ordered, it comes with many limitations. Qualitative immunoassays for benzodiazepines in urine are readily available but do not typically aid in acute management decisions. Most of these screening tests detect only benzodiazepines that are metabolized to oxazepam glucuronide. Some benzodiazepines such as clonazepam, lorazepam, midazolam, and alprazolam will not show up on many urine drug screens as a result. Also, a positive urine drug screen only indicates recent exposure but does not confirm causality for acute toxicity or overdose, nor does it name a specific agent.
The mainstay treatment for acute benzodiazepine toxicity is supportive care which may include endotracheal intubation to provide definitive airway management. Single-dose or multi-dose activated charcoal, hemodialysis, or whole bowel irrigation play no role in the management of benzodiazepine toxicity.
While the mainstay treatment of acute benzodiazepine toxicity or overdose is supportive care, there is, however, an “antidote” that may be used in limited situations. Flumazenil is a nonspecific competitive antagonist at the benzodiazepine receptor that can reverse benzodiazepine induced sedation. However, in most cases, the risks of flumazenil usually outweigh the benefits in acute toxicity, and thus flumazenil is not recommended for routine reversal of this sedative agent. Seizures and cardiac dysrhythmias, particularly PSVT can occur after flumazenil administration, and many fatalities have been reported. Flumazenil can precipitate acute withdrawal syndromes in those with chronic benzodiazepine dependence which can be life-threatening. If a patient who has a chronic dependence to benzodiazepines is given flumazenil, it can lower their seizure threshold, and potentially cause life-threatening seizures. The treatment of seizures which typically involves benzodiazepines would be rendered useless, as the flumazenil has blocked the benzodiazepine receptors.
Flumazenil can be safely administered to the non-habituated user of benzodiazepines. This situation classically occurs in the pediatric population with accidental ingestion or the role of acute reversal after procedural sedation. It is recommended that the decision to use flumazenil be based on the balance of risk versus benefit in the assessment and treatment of a patient that is a non-habituated user of benzodiazepines; as most people with a BZD overdose will do well with supportive care and time alone.
The key to preventing benzodiazepine toxicity is the education of the healthcare worker about sound prescribing habits. Many cases of benzodiazepine overdose have occurred because high doses of the drugs have been prescribed for trivial complaints. The nurse and the pharmacist should also educate the patient on drug safety. The patient should be told to abstain from alcohol and other illicit agents while taking benzodiazepines. Further, any patient with an intentional overdose should be referred to a mental health counselor prior to discharge. The pharmacist must always check the database to ensure that the patient is not obtaining multiple prescriptions from other pharmacies. Medical providers and pharmacists must always be suspicious of patients who present with stories of lost prescriptions or repeat prescriptions. Before dispensing any benzodiazepine, the pharmacist should educate the patient on the dose, side effects, and duration of usage. If the pharmacist suspects the liberal prescribing of such drugs by any healthcare workers, then a report should be made to the local DEA office. Only through diligent and safer prescribing habits can the problem of benzodiazepine toxicity be decreased.
When benzodiazepines are ingested alone, they are rarely associated with a poor outcome, but when they are ingested with other agents like alcohol, opiates or other sedatives, there is a risk of morbidity and even death. All benzodiazepines can cause apnea but the risk is highest with alprazolam. With the availability of flumazenil, the risk of death is low. These drugs are good sedatives but they also have a risk of addiction and tolerance. Many people remain addicted to benzodiazepines because of empirical prescribing by healthcare workers. (Level V)
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