Continuing Education Activity

Benzodiazepines are a class of drugs that act upon benzodiazepine receptors (BZ-R) in the central nervous system. Benzodiazepines are especially important in the cessation of seizure activity, as 1% to 2% of emergency department visits annually in the United States are for seizures. Indications for benzodiazepine administration include but are not limited to anxiety disorders, insomnia, acute status epilepticus, induction of amnesia, spastic disorders, seizure disorders, and agitation. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, toxicology, and monitoring of the broad array of physiological possibilities when using benzodiazepines in the clinical setting.

Objectives:

• Identify the mechanism of action of the benzodiazepine class of drugs.
• Identify the FDA-approved indications for benzodiazepines.
• Review the adverse events of the benzodiazepines class of medicines.
• Outline interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with benzodiazepines, leading to optimal patient outcomes and minimizing adverse events.

Indications

Benzodiazepines are especially important in the cessation of seizure activity, as 1% to 2% of emergency department visits annually in the United States are for seizures. Indications for benzodiazepine administration include but are not limited to anxiety disorders, insomnia, acute status epilepticus, induction of amnesia, spastic disorders, seizure disorders, and agitation. Non-FDA-approved administration of benzodiazepines is commonly found in the field of psychiatry. Indications here include Tourette's syndrome, delirium, delirium tremens, sleep disorders, and "abnormal movements associated with medications.[1][2]

FDA-approved Benzodiazepines

• Alprazolam: Alprazolam is indicated for anxiety disorders and panic disorders, including agoraphobia.[3]
• Chlordiazepoxide: Chlordiazepoxide is primarily indicated for the management of alcohol withdrawal syndrome.[4]
• Clobazam: Clobazam is indicated for seizures associated with Lennox-Gastaut syndrome.[5]
• Clonazepam: Clonazepam is indicated for treating panic disorder and agoraphobia.[3] It is also indicated for the treatment of myoclonic seizures and absence seizures.[6]
• Clorazepate: Clorzapte is used for adjunct treatment of short-term management of anxiety disorders. It is also indicated for focal (partial) onset seizures.[7]
• Diazepam: Diazepam is used for alcohol withdrawal management,[7] Rectal diazepam is also indicated for treating febrile seizures.[8]
• Estazolam: According to the American Academy of Sleep Medicine, estazolam is indicated for the treatment of insomnia.[9]
• Flurazepam: Flurazepam is indicated for the treatment of insomnia.[9]
• Lorazepam: Lorazepam is used for anxiety disorders. According to American Epilepsy Society guidelines, parenteral lorazepam is one of the first-line treatments for convulsive status epilepticus.[10]
• Midazolam: Midazolam is indicated for convulsive status epilepticus and procedural sedation. Midazolam is used for sedation in mechanically ventilated patients in the MICU/SICU.[11]
• Oxazepam: Oxazepam is indicated for anxiety disorders, and according to the ASAM (American Society of Addiction Medicine) guidelines, oxazepam is indicated for alcohol withdrawal syndrome.[12]
• Quazepam: According to the American College of Physicians, quazepam is indicated mainly for treating chronic insomnia in adults.[13]
• Temazepam: American Academy of Sleep Medicine (AASM) clinical practice guideline suggests temazepam for sleep onset and sleep maintenance insomnia.[9]
• Triazolam: Triazolam is indicated primarily for sleep-onset insomnia.
• Remimazolam: Remimazolam was approved by the FDA in 2020 and is indicated for short(<30 mins) procedural sedation in adults.[14]

Mechanism of Action

Benzodiazepines are a class of drugs that act upon benzodiazepine receptors (BZ-R) in the central nervous system (CNS). The receptor is a protein comprised of five transmembrane subunits that form a chloride channel in the center, i.e., the GABA-A receptor. The five subunits comprised of two alpha subunits, two beta subunits, and one gamma subunit. The extracellular portions of the alpha and beta subunit proteins form a receptor site for gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. The extracellular portions of the alpha and gamma subunit proteins form a binding site for benzodiazepines. Activation of the BZ-R causes a conformational change to a central pore, which allows the entrance of chloride ions into the neuron. The influx of the chloride anion results in hyperpolarization of the neuron resulting in CNS depression.[15] It is important to recognize that benzodiazepines increase the frequency of opening of the GABA-A receptor Cl– channel in the presence of GABA. In the absence of GABA, benzodiazepines have no effects on GABA-A receptor function.[16]

Pharmacokinetics

Absorption:  After oral administration, benzodiazepines are usually well absorbed from GIT except for clorazepate which is decarboxylated in gastric juice before absorption. After intramuscular injection, the absorption of diazepam or chlordiazepoxide is slow, and the absorption of lorazepam or midazolam is usually quick. After intravenous administration, benzodiazepines quickly distribute to the brain and the central nervous system. Midazolam is one of the most lipophilic benzodiazepines, due to which there is a quick crossing of the blood-brain barrier and rapid onset of clinical effects.

Distribution: The benzodiazepines and their active metabolites avidly bind to plasma proteins. Plasma protein binding for alprazolam is approximately 70%, 85% for clonazepam, and 99% for diazepam. The concentration of benzodiazepines in the CSF is approximately equal to the concentration of free drugs in plasma.   Diazepam is redistributed especially rapidly.

Metabolism: the first phase of metabolism involves the formation of N-desalkylated metabolites that are biologically active. Exceptions are triazolam, alprazolam and midazolam. The second phase of metabolism involves hydroxylation and usually yields an active derivative. The third phase of metabolism is the conjugation with glucuronic acid. Most benzodiazepines are metabolized extensively by hepatic CYP3A4 and CYP2C19. Lorazepam undergoes direct glucuronidation without cytochrome p450 metabolism. Consequently, lorazepam can be used in patients with hepatic dysfunction.[17] Remimazolam is degraded to metabolite(CNS7054), which has negligible hypnotic activity.[18]

Excretion: Benzodiazepines and their metabolites are primarily excreted by the kidney. Diazepam produces the active metabolites oxazepam, temazepam, and desmethyldiazepam, which further increase the drug action duration. The elimination half-life of benzodiazepines is increased in the elderly and patients with renal dysfunction.[19]

Administration

Benzodiazepines are commonly administered via the oral and intravenous routes. They may also be administered rectally, intranasally, and intramuscularly, as protocol/patient presentation dictates. For example, intranasal or intramuscular administration may be useful in actively seizing patients where intravenous (IV) or oral administration cannot be safely performed. Rectal administration in pediatric patients may be used for seizure cessation when IV access has not been established. Benzodiazepine administration can be performed by providing small doses of the medication until the desired effect (i.e., sedation, cessation of seizure activity, anxiolysis) has been achieved. However, it should be noted that it may take 3 to 5 minutes to achieve a CNS drug concentration adequate to produce the desired effect with intravenous administration. Therefore, adequate time between doses should be allowed to prevent oversedation of the patient. Additionally, resuscitation and airway management equipment must be readily available to providers during the administration of benzodiazepines. Airway management equipment may include nasopharyngeal or oropharyngeal airways, bag valve masks, blind insertion airway devices, laryngeal mask airways, or endotracheal intubation as training of emergency management service providers allows.

Dosage Recommendations

Alprazolam: For generalized anxiety disorder, initiate treatment with a dose of 0.25 mg to 0.5 mg three times daily. The dose of alprazolam may be increased at intervals of 3 to 4 days to a daily dose of 4 mg. For panic disorders, a 1-4 mg daily dose is used. Use the minimal effective clinical dose due to the potential for dependence.[3]

Chlordiazepoxide: For alcohol withdrawal syndrome, the suggested initial dose is 50 to 100 mg, followed by repeated doses of up to 300 mg per day as needed. Adjust the dose according to CIWA-Ar protocol.[20]

Clonazepam: The initial dose for adults with panic disorder is 0.5 mg daily. The maintenance dose for most patients of 1 mg per day. 0.5 mg is given thrice daily for seizure disorders, and the maximum recommended daily dose is 20 mg.

Clobazam: For Lennox-Gastaut syndrome, an adjunct to antiepileptic drugs, the initial dose is 10 mg for patients weighing more than 30 kg. The dose is increased to 20 mg after one week. The usual maintenance dose after two weeks is 40 mg. In patients with a weight <30 kg, the dose should be reduced to half the recommended dose mentioned above. Study findings indicate that patients with seizure improvement on starting dosages of 10 to 20 mg/day of clobazam may have better seizure control even if the dosage is increased beyond the maximum recommended dosage of 40 mg/day.[5]

Clorazepate: The initial dose in patients with focal (partial) onset seizures in patients over 12 years is 7.5 mg three times a day. The maximum recommended dose is 90 mg/day.[7]

Diazepam: ASAM 2020 guidelines recommend front-loading for patients experiencing severe alcohol withdrawal (e.g., CIWA-Ar ≥ 19). A withdrawal symptom severity scale guides a front-loading regimen (e.g., 10 mg diazepam orally every hour if CIWA-Ar score ≥10) or according to a fixed schedule (e.g., 20 mg diazepam orally every 2 hours for three doses).[12] The recommended dose of diazepam (rectal) for febrile seizures is 0.5 mg/kg.[8][21]

Estazolam: According to AASM, the dose of estazolam for sleep onset and sleep maintenance insomnia is 1 to 2 mg at bedtime.[9]

Flurazepam: Flurazepam is indicated for the treatment of insomnia. The recommended dose of flurazepam is 15 mg for women and 30 mg for men.

Lorazepam: According to AES guidelines, IV lorazepam(0.1 mg/kg) is administered as an initial dose for convulsive status epilepticus; the maximum recommended dose is 4 mg. The dose may be repeated at 3 to 5 minutes.[10]

Midazolam: Midazolam is administered 10 mg IM for convulsive status epilepticus as a single dose. Midazolam is preferred for patients without IV access. Intranasal midazolam (0.2 mg/kg, maximum dose, 10 mg) can be used in prehospital settings. (AES guidelines). For procedural sedation in patients< 60 years of age, 0.5 to 2.5 mg IV should be administered slowly over at least 2 minutes. Clinicians should fully evaluate the sedative effect before administering another dose. In MICU/SICU, midazolam is used as an alternative agent for sedation in mechanically ventilated patients. An intermittent dosing strategy is preferred to avoid drug accumulation. It is administered with a RASS goal of 0 to -2.[11][22][23]

Oxazepam: For alcohol withdrawal syndrome, oxazepam is administered with a symptom-triggered dosing approach. For CIWA-Ar scores between 8 to 15, 15 mg oxazepam is administered and 30 mg oxazepam is given for CIWA-Ar >15).(ASAM 2020 guidelines).[12]

Quazepam: Quazepam is suggested as an alternative drug for sleep onset and sleep maintenance insomnia. The recommended dose is 7.5 mg once daily at bedtime. The dose of quazepam can be increased to 15 mg, but the drug has a long half-life; hence there is a concern regarding accumulation and daytime impairment.[13]

Temazepam: AASM Clinical Practice Guideline recommends temazepam for sleep onset and sleep maintenance insomnia. The recommended dose is 7.5 to 15 mg once daily at bedtime. Temazepam improves total sleep time, decreases sleep latency, and improves sleep quality. According to the ACP (American College of Physicians) guidelines, all patients with chronic insomnia should receive cognitive behavioral therapy as the initial treatment intervention.[9][13]

Triazolam: Triazolam is indicated primarily for sleep-onset insomnia. The recommended dose is 0.125 to 0.25 mg once daily at bedtime. Limit the use to 4 to 8 weeks.[12]

Remimazolam: Remimazolam was approved by the FDA in 2020 and is indicated for short (<30 mins) procedural sedation in adults. For procedural sedation in adult patients, administer 5 mg IV remimazolam over 1 minute. To maintain procedural sedation, administer 2.5 mg IV (as needed) over 15 seconds. For induction, in ASA( American Society of Anesthesiologists) class III and IV patients, administer 2.5 mg to 5 mg IV over 1 minute based on the clinical condition. To maintain procedural sedation in ASA class III and IV patients, administer  1.25 mg to 2.5 mg intravenously as needed over 15 seconds. Wait for at least 2 minutes before administration of an additional dose.[14]

Use in Specific Patient Populations

Patients with Hepatic Impairment: Lorazepam and oxazepam metabolism is minimally affected by liver disease. As discussed above, lorazepam is the safest empiric choice among benzodiazepines for treating alcohol withdrawal syndrome and in patients with hepatic impairment. Administer remimazolam with caution in severe hepatic impairment.[24]

Patients with Renal Impairment: In renal impairment, there is decreased clearance and plasma protein-binding, resulting in increased unbound(active) concentration of benzodiazepine. According to a study, lorazepam may be safe in patients with ESRD. There is a risk of accumulation with diazepam. Lower starting doses should be used, and the dose should be cautiously titrated to clinical response.[19][25]

Pregnancy Consideration: Most benzodiazepines are classified as former FDA pregnancy category D, indicating some fetal risk, but potential benefits may allow the use in pregnant women. (In seizures where fetal mortality increases by 10% for every minute of maternal seizure activity). Several studies have indicated that specific benzodiazepines (diazepam and chlordiazepoxide) may increase the risk of congenital malformations, including cleft palate in the fetus. Others, such as flurazepam and temazepam, are considered pregnancy class X drugs, as they have been shown to produce neonatal lethargy and problems in skeletal development (exencephaly and fusion or asymmetry of ribs) in neonates, respectively. All benzodiazepines should be particularly avoided during the first trimester of pregnancy.[26] According to NICE guidelines, clinicians should not suggest benzodiazepines to pregnant women; however, benzodiazepines can be used to manage severe anxiety, agitation, and seizures. The use of benzodiazepines during pregnancy is associated with neonatal hypotonia and withdrawal. Counseling is important to taper down benzodiazepines in women who are planning for pregnancy.[27][28]

Breastfeeding Considerations: Care should be taken in the neonatal and pre-term infant populations, as studies indicate these patients experience significant hypotension, particularly with co-administration of opioids, specifically fentanyl. A safety scoring system suggests that midazolam, lorazepam, and oxazepam can be used cautiously. The use of benzodiazepines during lactation should be avoided unless there is a compelling indication.[29][30][31]

Adverse Effects

Common adverse effects of benzodiazepine administration include, but are not limited to:

• Respiratory depression
• Respiratory arrest
• Drowsiness
• Confusion
• Headache
• Syncope
• Nausea/vomiting
• Diarrhea
• Tremor

In neonates, less than 1% of patients treated with benzodiazepines experience laryngospasm and bronchospasm. They may also experience ventricular arrhythmias, including ventricular bigeminy or premature ventricular contractions, vasovagal syncope, bradycardia, or tachycardia. Gastrointestinal reactions may include retching, nausea/vomiting, and excess salivation. CNS and neuromuscular adverse effects may include euphoria, hallucination, ataxia, dizziness, seizure-like activity, and paresthesia. Visual disturbances may include diplopia (“double vision”), cyclic eyelid movement, loss of balance, and difficulty focusing the eyes on objects. Long-term use of benzodiazepines can lead to cognitive impairment.[32] Rare cases of cholestatic liver injury have been reported with benzodiazepines like alprazolam, clonazepam, diazepam, and flurazepam.[33] Hypertension, as well as hypotension, is observed with remimazolam. Monitor the blood pressure during the procedure.[34]

Drug-Drug Interactions

• Benzodiazepines may interact with ethanol, other benzodiazepines, and sedatives such as barbiturates, resulting in increased respiratory depression via a synergistic effect. Therefore, concomitant administration of benzodiazepines with patients under the influence of the preceding drugs should be carefully performed, with respiratory monitoring in place.[35]

• Lorazepam and oxazepam are metabolized by UGT (Uridine diphosphate glucuronosyltransferases). Inducers of UGT, such as carbamazepine, phenobarbital, phenytoin, and rifampin, may induce the metabolism and decrease the efficacy.[7]

• Excessive sedation can result from concurrent administration of benzodiazepine-like midazolam, triazolam, alprazolam, or diazepam administered with strong CYP3A4 inhibitors like itraconazole, ketoconazole, grapefruit juice, clarithromycin, nefazodone, ritonavir. Avoid concurrent administration.[36][37]

Contraindications

• Contraindications of benzodiazepines include a known case of angle-closure glaucoma. Benzodiazepines have muscle relaxant effects that can affect the function of the sphincter pupillae muscle of the iris.[38]

• Benzodiazepines are also contraindicated in patients with prior hypersensitivity reactions. Anaphylaxis and angioedema have been reported.[39]  Remimazolam is contraindicated in patients with a history of hypersensitivity reaction to dextran 40.[40]

Box Warning:  Concomitant use of benzodiazepines with opioids can lead to sedation, severe respiratory depression, coma, and death. Avoid combination.[41]

Monitoring

Benzodiazepines are CNS depressants specifically inhibiting respiratory drive. Therefore, careful monitoring of all vitals, especially blood pressure and respiratory rate, should be performed after the administration of benzodiazepines. In addition, waveform capnography should be considered to monitor respiratory status. Though the therapeutic index of benzodiazepines is high, monitoring respiratory depression is critical. Respiratory arrest has been noted to occur with rapid injection of benzodiazepines via the intravenous route.[42]

Monitor for alcohol withdrawal using clinical institute withdrawal assessment-alcohol, revised (CIWA-Ar) protocol, and adjust the dose of benzodiazepines according to the score.[20] Patients receiving parenteral lorazepam or diazepam for alcohol withdrawal should be monitored for signs of hyponatremia and metabolic acidosis, as the IV formulation contains propylene glycol.[12]

Monitor Richmond Agitation Sedation Scale(RASS) in patients administered benzodiazepines in mechanically ventilated patients. According to the Society of Critical Care Medicine (SCCM) guidelines, an individualized patient-centered approach should be used to prevent oversedation.[22][23][43]

Healthcare professionals can use prescription drug monitoring programs (PDMP) to identify benzodiazepine misuse.[44]

Toxicity

Benzodiazepine overdose requires managing the airway, breathing, and circulation according to AHA guidelines.[45] Flumazenil is a GABA-A receptor antagonist, acting to reverse the sedative effects of benzodiazepines. Flumazenil functions through competitive inhibition of the alpha-gamma subunit of the GABA-A receptor. Flumazenil administration should be done judiciously, as it may precipitate withdrawal seizures. Of note, one multi-center trial found that patients with excessive benzodiazepine ingestion could become “re-sedated” after flumazenil began to wear off. Naloxone may also be administered if patient history/presentation suggests that opioids were taken along with benzodiazepines and the patient is experiencing signs of respiratory distress/arrest. However, naloxone doses may be smaller than the standard 0.4 mg in suspected benzodiazepine and opioid co-ingestion. Doses of 0.05 mg may be recommended, as a withdrawal from opioids may precipitate vomiting. This becomes an issue in sedated benzodiazepine-overdosed patients, as they may be unable to protect their airways.[46][47] The activated charcoal administration is contraindicated in benzodiazepine overdose. This is due primarily to altered mental status commonly associated with benzodiazepine overdose, which increases the risk of aspiration of activated charcoal.[48]

Enhancing Healthcare Team Outcomes

Benzodiazepines are commonly prescribed drugs in outpatient and hospitalized patients. Benzodiazepines are effective for sedation and anxiolysis; they also have the potential to cause harm. All healthcare professionals, including clinicians (MD, DO, NP, PA) who prescribe these agents, must be fully aware of the drug's adverse effects, misuse, abuse, and potential to develop physical dependence. Benzodiazepines are DEA-scheduled IV drugs. Pharmacists should perform medication reconciliation and report to clinicians in case of significant drug-drug interaction. Anesthesiologists and CRNA (certified registered nurse anesthetists) have a vital role in procedural sedation.

Nurses have an important role in monitoring patients in mechanically ventilated patients. Neurologists should be consulted for the appropriate use of benzodiazepines like clobazam for Lennox-Gastaut syndrome. Intensivists have an important role when benzodiazepines are used for sedation in mechanically ventilated patients. Emergency medicine physicians and nurses should rapidly stabilize the patient in overdose. Once the patient is stable, the psychiatrist should be consulted. Psychiatrists play a crucial role in patients suffering from benzodiazepine use disorder. Finally, liberal prescribing of these drugs is not recommended as their abuse potential is high. Additionally, the DEA has been clamping down on healthcare professionals who prescribe these agents without a valid reason and no documentation.[49][50] 

As illustrated above, benzodiazepine therapy requires the collaborative approach of an interprofessional healthcare team of clinicians, specialists, pharmacists, and specialty-trained nurses working together to accomplish optimal patient outcomes. A study concluded that interprofessional team-based models that include clinical pharmacists and primary care physicians for anxiety and insomnia could assist in optimizing therapy and minimizing the risk associated with benzodiazepine use.[51] [Level 5]