Benzodiazepines

• Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are the pharmacologic treatments of choice for all anxiety disorders. Benzodiazepines are best employed in the short-term treatment of symptoms of acute anxiety, as temporary adjuncts to SSRIs or SNRIs during treatment initiation, and for temporary use during periods of anxiety exacerbation during long-term treatment.[50542][50550][50824][50827][50829][70703]
• In children and adolescents, benzodiazepines have not demonstrated efficacy for the treatment of anxiety disorders in a small number of clinical trials and are not recommended by the American Academy of Child and Adolescent Psychiatry for this indication.[67322]

Comparative Dosing for Anxiety

*OBRA supplies dosage guidance for older (geriatric) adults in long-term care facilities - in these settings, if a higher daily dose is needed, documentation of necessity is required; when any medication is used to induce sleep, treat a sleep disorder, manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity per the OBRA guidelines.[27748]

Seizure Disorders in Pediatric Patients

• According to evidence-based guidelines by the American Epilepsy Society, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes in children with convulsive status epilepticus while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective. No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in children with convulsive status epilepticus.[61569]
• Clobazam is used for the adjunct treatment of seizures associated with Lennox-Gastaut syndrome children aged 2 years and older (an orphan drug designation).[46370]
• Clonazepam is indicated for the treatment of absence seizures, petit mal variant (Lennox-Gastaut syndrome), and akinetic and myoclonic seizures in infants, children, and adolescents.[28444]
• All patients and their caregivers should have an emergency seizure treatment plan.

Seizure Disorders in Adult Patients

• According to evidence-based guidelines by the American Epilepsy Society, intramuscular midazolam, intravenous lorazepam, and intravenous diazepam are established as efficacious as initial therapy for convulsive status epilepticus. Intramuscular midazolam is superior to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access. No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults with convulsive status epilepticus.[61569]
• Clobazam is used for the adjunct treatment of seizures associated with Lennox-Gastaut syndrome.[46370]
• Clonazepam is indicated for the treatment of absence seizures, petit mal variant (Lennox-Gastaut syndrome), and akinetic and myoclonic seizures.[28444]
• All patients and their caregivers should have an emergency seizure treatment plan.

• Benzodiazepines have largely been replaced by the nonbenzodiazepine benzodiazepine-receptor agonists (e.g., eszopiclone, zaleplon, zolpidem), the orexin receptor antagonist (daridorexant, lemborexant, suvorexant), melatonin analogs (e.g., ramelteon), and tricyclic antidepressant-class sedatives (e.g., doxepin) due to concerns of dependence, tolerance, and the relatively unfavorable side effect profile of benzodiazepines.[41506][50830][62207]
• Within the benzodiazepine class, the shorter half-life, rapid onset of action, and lack of active metabolite make temazepam particularly suitable for this indication. Problematic rebound insomnia upon discontinuation and pronounced anterograde amnesia are major drawbacks to the use of triazolam.

Comparative Dosing for Insomnia

* OBRA supplies dosage guidance for older (geriatric) adults in long-term care facilities - in these settings, if a higher dose is needed, documentation of necessity is required; when any medication is used to induce sleep, treat a sleep disorder, manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity per the OBRA guidelines [27748]

a The approximate equivalence is based on data from clinical trials and meta-analyses comparing 2 or more benzodiazepines for insomnia; this approximation may not represent the equivalence for other indications

• Benzodiazepines are one of several classes of drugs used for their tranquilizing effect in agitated patients.
• Midazolam is the most commonly used parenteral agent in hospital settings (e.g., ICU, emergency department) and for surgical and procedural sedation.
• The pharmacokinetic properties and multiple routes of administration of lorazepam make this benzodiazepine suitable in treating agitation of various etiologies and severities.

Benzodiazepines cause dose-dependent respiratory depression. Respiratory depression can be characterized by apnea, hyperventilation, hypoventilation, or respiratory failure. When ingested with other CNS depressants or respiratory depressants, such as opioid analgesics or alcohol, the result can be fatal, particularly with overdose. Flumazenil, a parenteral benzodiazepine antagonist, is a rapidly acting and effective treatment for benzodiazepine overdose. Flumazenil is administered only by rapid IV injection because it is highly irritating, and care should be taken to avoid extravasation. Because the duration of action for some benzodiazepines may be much longer than that of flumazenil (half-life in brain of about 0.5 hours, terminal half-life of about 1 hour), repeat doses of flumazenil may be necessary.[50837][50838][61143]

Anterograde amnesia, somnolence, fatigue, impaired balance/coordination, and impaired thinking are dose-related neurologic effects of benzodiazepines. Tolerance to many of these effects often develops over a few weeks. These events are more commonly seen in patients taking other CNS depressants and when consuming alcohol; patients should be strictly cautioned about these additive effects. Although uncommon, paradoxical CNS stimulation can occur with any benzodiazepine; possible symptoms include insomnia, nightmares, excitement, irritability, and aggression. Discontinuation of the benzodiazepine is the most effective management strategy when CNS stimulation occurs. Also, disinhibition and subtle executive dysfunction have been reported with both acute and chronic use of benzodiazepines, and are among the many reasons that long-term use of these agents for anxiety is generally not recommended.[50828]

Benzodiazepine use increases the risk of falls in older patients by approximately 50%. Risk is largely driven by daily dose, but patients newly started on benzodiazepines are also at heightened risk. According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) in geriatric patients and avoidance is generally recommended, although some agents may be appropriate for seizure disorders, rapid eye movement sleep disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, peri-procedural anesthesia, or end-of-life care. Older adults have an increased sensitivity to benzodiazepines, and, in general, all benzodiazepines increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults.[50840][63923]

Physiologic benzodiazepine dependence occurs as a natural consequence of regular use of benzodiazepines and does not, in and of itself, indicate drug misuse or abuse. Physiologic dependence to benzodiazepines can occur with therapeutic doses administered for as few as 3 to 6 weeks and with a very high prevalence within 4 months to 1 year of continued treatment. The risk of dependence increases with higher daily dosages and long-term treatment. During treatment discontinuation, the benzodiazepine should be slowly tapered to minimize the risk of withdrawal.[50828]

Withdrawal symptoms are common if the benzodiazepine is stopped abruptly or withdrawn too quickly. In general, withdrawal symptoms are more likely to occur and be of greater intensity with benzodiazepines that have a short duration of action, such as alprazolam. Panic rebound may be particularly problematic for patients receiving higher doses for panic disorder. Patients with a history of a seizure disorder or who are taking other drugs that lower the seizure threshold (e.g., tricyclic antidepressants, phenothiazines) should not be withdrawn abruptly from benzodiazepines because of the risk of precipitating seizures, including status epilepticus. During withdrawal, the greatest risk of seizure appears to be during the first 24 to 72 hours. All benzodiazepines, and especially those with a short half-life, should be withdrawn slowly, using a gradual tapering schedule. Switching patients from a short half-life benzodiazepine to a benzodiazepine with a longer half-life, such as clonazepam, is one possible strategy when tapering towards discontinuation. If discontinuing the originally prescribed short-acting benzodiazepine, it may be advisable to reduce the individual doses before reducing the frequency of administration. Psychotherapeutic support may help to achieve a successful outcome.[50828]

A boxed warning in the labels for all benzodiazepines warns about the risks of coadministration of benzodiazepines and opioids. Concomitant use of benzodiazepines and opioids increases the risk of respiratory depression, low blood pressure, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and prescription durations to the minimum required, and monitor patients for signs and symptoms of respiratory depression and sedation.[61143]

Concomitant administration of benzodiazepines with other CNS depressant drugs, including alcohol, also generally produces additive CNS depressant effects. Patients should be advised to avoid ingestion of alcoholic beverages during treatment with a benzodiazepine. In addition to alcohol, medications such as psychotropic medications, anticonvulsants, sedating antihistamines, and many other medications that produce CNS sedation may have additive effects with the benzodiazepines.[62827]

Many benzodiazepines are metabolized by CYP450 enzymes, particularly CYP3A4 and/or CYP2C19, and may require dosing adjustments when prescribed to patients receiving inhibitors or inducers of the relevant CYP450 enzymes for that benzodiazepine. For example, triazolam is a sensitive CYP3A4 substrate, and coadministration with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, lopinavir, ritonavir) is contraindicated. Dose reductions of up to 50% may be required when alprazolam, a CYP3A4 substrate, is given concomitantly with CYP3A4 inhibitors. Dosage reductions of clobazam, a CYP2C19 substrate, may be required when used concomitantly with CYP2C19 inhibitors. Diazepam is also a moderately sensitive CYP2C19 substrate. Increased monitoring of benzodiazepines metabolized by CYP450 enzymes is recommended when used with CYP450 inhibitors or inducers.[41538][41543][46370][56579]

Grapefruit juice is a clinically significant inhibitor of CYP3A4. Benzodiazepines that are metabolized by CYP3A4 include midazolam, diazepam, and triazolam. The drug concentrations of the benzodiazepine may increase when consuming grapefruit juice. Consideration should be given to not drinking grapefruit juice when taking these medications. Also, alprazolam is metabolized by CYP3A4 but does not appear to be affected by grapefruit juice.[28040][30935][44717][41543][53391]

Oral contraceptives and other moderate to weak CYP450 inhibitors may increase concentrations of benzodiazepines metabolized via oxidative metabolism. Oral contraceptives also increase glucuronidation, which may decrease concentrations of benzodiazepines metabolized by glucuronidation.[30723][41538]

Benzodiazepines are relatively contraindicated in patients with a history of substance abuse due to the increased risk of addiction and abuse/misuse.[41543]

Benzodiazepines should be avoided, if possible, in patients with significant pulmonary disease, such as severe chronic obstructive pulmonary disease or sleep apnea, because they can exacerbate respiratory depression. In rare instances, death has occurred in patients with severe pulmonary disease shortly after the initiation of a benzodiazepine.[28712][41538]

In general, benzodiazepine use for the treatment of insomnia should be avoided during pregnancy, since other methods to treat insomnia may be considered. The use of benzodiazepines for seizures or other necessary indications during pregnancy should be limited to cases in which the benefit outweighs the risk. Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation, floppy infant syndrome (characterized by neonatal respiratory depression, lethargy, hypotonia) and/or withdrawal (also known as neonatal abstinence syndrome). Clinical manifestations of neonatal abstinence syndrome may include hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties. The incidence, time to onset, and duration of floppy infant syndrome and/or neonatal abstinence syndrome is multi-factorial and dependent on characteristics of the benzodiazepine used (e.g., duration of use, drug lipophilicity, placental disposition, degree of accumulation in neonatal tissues). Neonates exposed to benzodiazepines during pregnancy, labor, or obstetric delivery should be monitored closely for both of these conditions and managed accordingly.[28712][41554][41538][28040][41533][62732][61318]

Many benzodiazepines distribute into breast milk and have the potential for accumulation and adverse effects in the nursing infant, including sedation and feeding difficulties. For this reason, benzodiazepines are not recommended during breast-feeding. The use of long-acting benzodiazepines, such as diazepam and clobazam, should be avoided in lactating individuals who are breast-feeding. If short-term or occasional maternal therapy with a benzodiazepine is required, medications with shorter half-lives and low passage into breast milk, such as lorazepam or oxazepam, may be reasonable alternatives for some patients. In some cases, there are recommendations to pump and discard breast milk (for approximately 5 half-lives) for certain benzodiazepines if such therapy is essential. Breastfed infants exposed to benzodiazepines via breast milk should be monitored frequently for symptoms of overexposure including lethargy, somnolence, poor sucking reflex, and poor weight gain. A single dose of a benzodiazepine, such as for acute treatment or a procedural purpose, does not appear to require any limitation.[61269][60685]

Older adults have an increased sensitivity to benzodiazepines. Geriatric adults may have a decreased elimination of some benzodiazepines by 50% or more, which may intensify or prolong the actions and adverse effects of these agents. The benzodiazepines may increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. Polypharmacy may increase the likelihood of drug interactions and adverse events. According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) in geriatric adults and avoidance is generally recommended, although some agents may be appropriate for seizure disorders (e.g., diazepam for acute seizure treatment), rapid eye movement sleep disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, peri-procedural anesthesia, or end-of-life care. The Beers panel also recommends avoidance in older adults with delirium, dementia, or a history of falls or fractures. If a benzodiazepine must be used, then lower dosages and close monitoring are recommended. Consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. If a benzodiazepine must be used, lorazepam or oxazepam may be preferred for use in the older adult because these benzodiazepines have no active metabolites, relatively few drug interactions, and shorter half-lives than most other drugs in the class.[50840][63923]

Benzodiazepines have specific and limited uses in pediatric patients, including the treatment of status epilepticus and for anesthesia/conscious sedation in the hospital or office setting. Clobazam and clonazepam are approved for the chronic treatment of specific seizure types in pediatric patients. The routine use of benzodiazepines for the treatment of anxiety or insomnia in pediatric patients is generally not recommended.[61149][63272][67322]