Benzodiazepines

Pharmacology/Mechanism of Action

Benzodiazepines exert their pharmacodynamic effects primarily through modulation of the gamma-aminobutyric acid type A (GABA-A) receptor, the principal inhibitory receptor subtype in the CNS. GABA is an inhibitory neurotransmitter that acts at GABA-A and GABA-B receptors, with GABA-A being the primary site of benzodiazepine activity.^[65276] Benzodiazepines bind to a benzodiazepine-specific allosteric site on the GABA-A receptor complex, enhancing the inhibitory effects of GABA by increasing the frequency of GABA-mediated chloride channel opening. This results in neuronal hyperpolarization and reduced neuronal excitability. Through these effects, benzodiazepines can produce varying degrees of CNS depression, including anxiolysis, sedation, hypnosis, amnesia, skeletal muscle relaxation, and anticonvulsant activity. Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors, including BNZ-1 receptors in the cerebellum and cerebral cortex, BNZ-2 receptors in the cerebral cortex and spinal cord, and BNZ-3 receptors in peripheral tissues. Benzodiazepines bind non-selectively to BNZ-1 and BNZ-2 receptors, enhancing GABA-mediated inhibition.^{[50829][52066]}

Although benzodiazepines are typically subdivided into short, intermediate, and long half-life agents, the pharmacokinetics of benzodiazepines are more complex. Some benzodiazepines have active metabolites whose pharmacokinetic properties need to be incorporated in the overall evaluation of the parent drug. In addition, benzodiazepines have a 2-compartment pharmacokinetic model of distribution, with a rapid central compartment phase followed by a redistribution phase, primarily to adipose tissue, which ultimately determines the duration of action. One consequence of this model is that lipophilic benzodiazepines, such as diazepam and chlordiazepoxide, are stored in adipose tissue and have extremely long half-lives. A second consequence, however, is that a single dose of a less lipophilic benzodiazepine, such as lorazepam, will remain at therapeutic concentrations at GABA-A receptors longer than the more highly lipophilic compounds that redistribute rapidly to adipose tissue.^[50830]

Comparison of Benzodiazepine Pharmacology

*Pro-drug which is converted to an active moiety

Therapeutic Use

General Benzodiazepine Use and Tapering recommendations:

• The risks and benefits of ongoing benzodiazepine use should be assessed every 3 months or as clinically indicated.

• Individuals who are candidates for discontinuation should be assessed for risks of withdrawal prior to stopping the medication; individuals who are likely to be physically dependent on the benzodiazepine should be tapered off the medication rather than having an abrupt discontinuation. While most tapers can be managed outpatient, patients at imminent risk of harm related to continued use (e.g., drug interactions, falls, or overdose), those with concomitant physical or mental health conditions that may complicate the safe tapering, and those with current or anticipated severe or complicated withdrawals may require inpatient care.

• Tapering strategies should be patient-specific and may be adjusted as needed to address withdrawal symptoms. Initial dose reductions of 5% are recommended, with an assessment of tolerability made. In general, the pace of benzodiazepine tapering should include dose reductions of 5% to 10% every 2 to 4 weeks and should not exceed 25% every 2 weeks.

• Individuals at risk of physical dependence, such as those taking a higher dose for more than a year, may require a conservative taper of 5% to 10% every 6 to 8 weeks or slower, depending on symptoms. Those with lower risks of physical dependence or who tolerate the initial dose reduction may be able to reduce the dose by 10% to 25% every 2 to 4 weeks.

• If withdrawal symptoms occur and interfere with the taper (e.g., sleep difficulty or anxiety), the taper may be paused or further slowed. Adjunctive medications may also be considered.^[73206]

Anxiety Disorders

• 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 or panic attacks, as temporary adjuncts to SSRIs or SNRIs during treatment initiation, and for temporary use during periods of anxiety exacerbation during long-term treatment.^{[51212][65204][65209][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; SSRIs are generally first-line treatments.^[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

Seizure Disorders in the Pediatric Populaton

• Numerous guidelines recommend benzodiazepines as initial therapy for management of pediatric status epilepticus. The American Epilepsy Society suggest intramuscular midazolam, intravenous lorazepam, or intravenous diazepam as first-line options; rectal diazepam, intranasal midazolam, and buccal midazolam are reasonable initial therapy alternatives when first-line agents are not available or cannot be administered.^[61569] Guidelines from the Canadian Pediatric Society recommend intravenous lorazepam or intravenous or intramuscular midazolam first-line.^[72226] Guidelines from the National Institute for Health and Care Excellence (NICE) vary depending on patient location, with intravenous lorazepam recommended for inpatient use and buccal midazolam or rectal diazepam suggested for individuals in the community without intravenous access.^[69871]

• Clobazam is used for the adjunct treatment of seizures associated with Lennox-Gastaut syndrome in 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 Adults

• Guidelines from the American Epilepsy Society suggest intramuscular midazolam, intravenous lorazepam, or intravenous diazepam for initial therapy in 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] Guidelines from the National Institute for Health and Care Excellence (NICE) vary, with intravenous lorazepam recommended first-line for inpatient use and buccal midazolam or rectal diazepam suggested for individuals in the community without intravenous access.^[69871]

• 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.

Sleep Disorders

• 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.^{[62207][73418]}

• Within the benzodiazepine class, the shorter half-life, rapid onset of action, and lack of active metabolites 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][60742]}

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

Agitation

• Current guidance suggests that benzodiazepine use in the treatment of agitation may vary by clinical setting or the underlying cause of agitation.

• Benzodiazepines remain particularly useful when agitation is related to alcohol withdrawal, benzodiazepine withdrawal, or stimulant intoxication, but they are not preferred for delirium unrelated to withdrawal or for acute alcohol/CNS depressant intoxication, where respiratory depression and oversedation are key concerns.^{[62910][73551]}

• The sedating and respiratory adverse effects of benzodiazepines may be particularly problematic in older adults requiring pharmacologic treatment for severe agitation, and benzodiazepine use should be avoided in this population when possible.^[73578]

• In the emergency department, the American College of Emergency Physicians guidance supports midazolam or lorazepam as part of combination regimens for severe agitation, while avoiding midazolam monotherapy when other options are available due to the risk of adverse effects.^[70065]

• In sedation/agitation management in the intensive care unit, the Society of Critical Care Medicine guidelines favor nonbenzodiazepine sedation strategies and do not recommend benzodiazepines as preferred routine agents.^[72981]

Comparative Efficacy

Summary

• Alprazolam has not been shown in clinical trials to be superior to comparator benzodiazepines in the treatment of panic disorder, with or without agoraphobia; but it has been associated with high rates of rebound anxiety, withdrawal symptoms, and a propensity for abuse.^[48980]

• In a systematic review, intravenous (IV) lorazepam was found to be equivalent in efficacy to IV diazepam and safer; children receiving IV lorazepam had less respiratory depression, fewer admissions to pediatric intensive care unit (ICU), and were less likely to need additional anticonvulsant medication to terminate seizures.^[20445]

• A meta-analysis of 6 studies comparing midazolam to diazepam found that midazolam by any route was superior to diazepam for seizure cessation and comparable to IV diazepam for seizure control.^[48984]

Comparative Efficacy Trials

Abbreviations: AEs, adverse events; DSM, Diagnostic and Statistical Manual; GAD, generalized anxiety disorder; HAM-A, Hamilton Anxiety Rating Scale; IV, intravenous; RR, relative risk; OR, odds ratio.

*p-value only shown if significant

Adverse Reactions/Toxicities

Respiratory depression / Overdose

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. 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.^{[61143][65896]}

Neuropsychiatric adverse effects

Benzodiazepines can cause dose-related central nervous system impairment, including somnolence, fatigue, anterograde amnesia, impaired concentration or thinking, executive dysfunction, and impaired balance or coordination. Tolerance to some sedative and psychomotor effects may develop after several weeks, but clinically meaningful impairment can persist, particularly with higher doses, long-acting agents, older age, or with concomitant use of central nervous system depressants or alcohol. Paradoxical reactions and central nervous system stimulation have been reported infrequently and may include insomnia, nightmares, agitation, excitement, irritability, aggression, disinhibition, and other behavioral changes. Benzodiazepines have also been associated with drug-induced cognitive decline and cognitive impairment after chronic exposure, and long-term benzodiazepine use for anxiety or insomnia is generally not recommended.^{[50828][73669]} One large cohort study found no association between the use of benzodiazepines and subsequent dementia, even with longer durations of cumulative use or the use of higher doses or longer-acting agents.^[73680]

Falls

According to the Beers Criteria, 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. Benzodiazepine use increases the risk of falls in older patients by approximately 50%. Risk is largely dose-dependent, but individuals newly started on benzodiazepines are also at heightened risk. Long-acting benzodiazepines also increase risks in the older adult, and if benzodiazepine use is medically necessary, short-acting agents are preferred for short durations only.^{[50840][63923]}

Drug dependence

Physiologic and psychologic dependence may occur with benzodiazepine use. Physiologic dependence with 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, benzodiazepines should be slowly tapered to minimize the risk of drug withdrawal.^{[50828][73668]}

Withdrawal syndrome

Withdrawal symptoms are common if a 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 individuals receiving higher doses for panic disorder. Individuals 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 abruptly withdrawn 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 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][73668]}

Drug Interactions

CNS depressants, including alcohol and opioids

A boxed warning is included in labels for all benzodiazepines warning about the risks of coadministration of benzodiazepines and opioids. Concomitant use of benzodiazepines and opioids increases the risk of significant sedation, respiratory depression, low blood pressure, and death. Reserve concomitant prescribing of these drugs for use in people 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][28712][41533]} Additionally, concomitant administration of benzodiazepines with other CNS depressant drugs, including alcohol, can result in additive CNS depression. Advise patients to avoid ingestion of alcoholic beverages during treatment with a benzodiazepine. Concomitant use of medications with CNS depressant effects, such as psychotropic medications, anticonvulsants, sedating antihistamines, should be avoided when possible to reduce the risk of additive CNS effects.^{[62827][28712][41533]}

Drugs that inhibit or induce CYP 450 isozymes

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

Grapefruit juice can inhibit CYP3A4, which may increase exposure to orally administered benzodiazepines that are CYP3A4 substrates by reducing first-pass metabolism. The interaction is most clearly demonstrated in oral midazolam and triazolam, where grapefruit juice can increase drug concentrations and sedation risk. Alprazolam is also metabolized by CYP3A4, and product labeling notes grapefruit juice as a possible interacting agent. Because the effects of grapefruit on benzodiazepines vary across products and individuals, advise avoidance of grapefruit juice when an oral benzodiazepine that is a CYP3A4 substrate is prescribed.^{[28040][30935][44717][41543][53391]}

Oral contraceptives

Oral contraceptives and other moderate to weak CYP450 inhibitors may increase concentrations of benzodiazepines that are metabolized via oxidative metabolism, such as lorazepam or alprazolam. Oral contraceptives also increase glucuronidation, which may decrease concentrations of benzodiazepines metabolized by glucuronidation.^{[30723][41538]}

Safety Issues

Respiratory depression and sedation

Benzodiazepines should be avoided when possible in people 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 individuals with severe pulmonary disease shortly after the initiation of a benzodiazepine. Respiratory depression and sedation may occur in any patient. Observational studies have demonstrated that concomitant use of opioids and benzodiazepines increases the risk of respiratory depression and drug-related mortality compared to use of opioids alone. If a decision is made to prescribe a benzodiazepine concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid, prescribe a lower initial dose of the benzodiazepine than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a benzodiazepine recipient, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation and not to use opioids concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of the medication have been determined, since benzodiazepines can cause sedation and psychomotor impairment.^{[28712][41538][61143][73665][73668]}

Hepatic impairment

The use of long-acting benzodiazepines, such as clonazepam and diazepam, should be avoided in people with severe hepatic impairment or failure. If benzodiazepine use is necessary in these individuals, agents that are shorter-acting, without active metabolites, and that undergo glucuronidation (e.g. oxazepam, lorazepam, or temazepam) may be preferred treatment options. The use of benzodiazepines in people with alcohol-related liver disease can also precipitate or worsen hepatic encephalopathy. Lower starting doses, close monitoring, and careful dose titration are recommended when use of these agents is necessary.^{[68581][71716]}

History of substance abuse

Benzodiazepines should be used with extreme caution in people with a history of substance abuse due to the increased potential for addiction and abuse/misuse.^[73668]

Pregnancy

In general, benzodiazepine use for the treatment of insomnia should be avoided during pregnancy, as other methods to treat insomnia may be considered. The use of benzodiazepines for mental health conditions, such as panic or anxiety disorders, should be limited to cases in which the benefit outweighs the risk. When benzodiazepines are indicated for emergent seizure control, such as status epilepticus, the benefits of rapid treatment generally outweigh potential fetal risks. 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 multifactorial 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.^{[61318][61572][62732][69871][73666]}

Breastfeeding

Many benzodiazepines are distributed into breast milk and have the potential for accumulation and adverse effects in the infant, including sedation and feeding difficulties. These concerns are increased with the use of long-acting benzodiazepines, such as clorazepate and chlordiazepoxide, and chronic use of these medications should be avoided during breast-feeding. Diazepam has a long half-life and active metabolites, increasing the risk of passage to a breastfed infant. However, emergent use as a dissolving film, nasal spray, or rectal gel for the acute management of seizures is appropriate and should not be withheld due to lactation concerns. If short-term or occasional therapy with a benzodiazepine is required for treatment of anxiety, medications with shorter half-lives and low passage into breast milk, such as lorazepam, alprazolam, or oxazepam, may be preferred; however, the choice of agent should also consider patient-specific factors. If used during lactation, benzodiazepines should be prescribed at the lowest effective dosage for the shortest duration. Infants exposed to benzodiazepines should be monitored for excessive sedation, slowed breathing rate, poor feeding, and inadequate weight gain. Following long-term exposure, the cessation of breast-feeding or cessation of benzodiazepine use during breast-feeding can lead to benzodiazepine withdrawal symptoms in the infant.^{[46229][60685][61269] [70364][70365]}

Geriatric adults

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. 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]}

Pediatric patients

Benzodiazepines have specific and limited uses in pediatric individuals, 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 the pediatric population. The routine use of benzodiazepines for the treatment of anxiety or insomnia in children and adolescents is generally not recommended.^{[61149][63272][67322]}