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Jul.30.2020

Benzodiazepines

Summary

  • Benzodiazepines, as a class, have been among the most commonly prescribed of all drugs, with a wide variety of indications, including insomnia, anxiety disorders, seizure disorders, anesthesia and peri-procedural sedation, skeletal muscle relaxation, and alcohol withdrawal.
  • Some benzodiazepines, such as lorazepam and diazepam, are used across most of the possible indications, whereas others are much more limited in their usage (e.g., clobazam is an orphan drug indicated only for the treatment of seizures associated with Lennox-Gastaut syndrome).
  • Within the class, individual drugs are differentiated primarily by their diverse pharmacokinetic profiles, which reflect large differences in half-life (long-acting, intermediate-acting, and short-acting), onset of action (rapid, intermediate, or slow), and metabolic outcomes (with or without active metabolites).
  • The pharmacokinetic profile is a major factor in determining the indications that are suitable to each particular benzodiazepine; for example, temazepam, with an intermediate onset of action, a 6- to 8-hour duration of action, and no active metabolites, is indicated exclusively for insomnia.
  • Physiologic dependence, which is accompanied by physical withdrawal symptoms, occurs as a natural consequence of regular use of therapeutic doses of benzodiazepines, without any drug misuse or abuse.
  • Psychological dependence is possible; therefore, this class of drugs is best avoided in patients with a history of substance abuse.

Pharmacology/Mechanism of Action

Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required, including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Extensive evidence indicates that benzodiazepines exert their effects through enhancement of the GABA-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is the primary site of benzodiazepine pharmacodynamic activity.[65276]

 

Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of benzodiazepine receptors are located in the CNS and other tissues: the BNZ-1 receptors are located in the cerebellum and cerebral cortex, the BNZ-2 receptors in the cerebral cortex and spinal cord, and the BNZ-3 receptors in peripheral tissues. Activation of the BNZ-1 receptor is thought to mediate sleep while the BNZ-2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ-1 and BNZ-2, which ultimately enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.[50829]

 

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

DrugOnsetDurationMetabolic PathwayMetabolites
AlprazolamRapidShortOxidative via CYP3A4Minimally active
ChlordiazepoxideIntermediateLongOxidative via CYP3A4Active
ClobazamSlowLongOxidative via CYP3A4 (primary), CYP2C19, and CYP2B6Active
ClonazepamRapidIntermediateOxidative via CYP3A4Inactive
Clorazepate*IntermediateLongHydroxylation and glucuronidationActive
DiazepamRapidLongDemethylation and hydroxylation via CYP3A4 and CYP2C19Active
EstazolamIntermediateIntermediateOxidative via CYP3A4Minimally active
FlurazepamRapidLongOxidative via CYP3A4Active
LorazepamRapidIntermediateGlucuronidationInactive
MidazolamRapidShortHydroxylation via CYP3A4Active
OxazepamSlowIntermediateGlucuronidationInactive
QuazepamIntermediateLongPartial CYP3A4Active
TemazepamIntermediateIntermediateGlucuronidationInactive
TriazolamRapidShortOxidative via CYP3A4Inactive

*Pro-drug which is converted to an active moiety

Therapeutic Use

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, 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]
  • 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. Very short-term use as initial adjuncts to an SSRI or SNRI to achieve rapid reduction in severe symptoms may be appropriate.[50832]

 

Comparative Dosing for Anxiety

DrugUsual Initial DoseDose RangeOBRA-specified MAXIMUM daily dose[60742]
Alprazolam

0.25 to 0.5 mg 3 times/day (adults)

0.75 to 4 mg/day0.75 mg/day

Chlordiazepoxide

(adults, adolescents, and children 6 years and older)

5 to 10 mg 3 to 4 times/day (adults)

5 mg 2 to 4 times/day (children 6 years and older)

15 to 100 mg/day (adults)

10 to 30 mg/day (pediatrics 6 years and older)

20 mg/day
Clonazepam

0.25 mg 2 times/day (adults)

0.5 to 4 mg/day1.5 mg/day
Clorazepate

15 mg 2 times/day (adults)

15 to 60 mg/day15 mg/day

Diazepam

(adults and pediatrics 6 months and older)

2 mg 2 to 4 times/day (adults)

1 to 2.5 mg 3 to 4 times/day (pediatrics 6 months and older)

4 to 40 mg/day (adults)

1 to 2.5 mg 3 to 4 times/day (pediatrics 6 months or older)

5 mg/day

Lorazepam

(adults, adolescents, and children 12 years and older)

1 mg 2 to 3 times/day (adults)

1 mg twice daily (children 12 years and older)

1 to 10 mg/day2 mg/day

Oxazepam

(adults and adolescents 13 years and older)

10 to 15 mg 3 to 4 times/day (adults and adolescents)30 to 120 mg/day30 mg/day

Seizure Disorders

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.

Sleep Disorders

  • Benzodiazepines have largely been replaced by the nonbenzodiazepine benzodiazepine-receptor agonists (e.g., eszopiclone, zaleplon, zolpidem), the orexin receptor antagonist (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][63262]
  • 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

DrugInitial DoseDose RangeOBRA-specified MAXIMUM dose [60742]Equivalent dose*
Estazolam0.5 to 1 mg at bedtime (adults)0.5 to 2 mg at bedtime0.5 mg at bedtime1 mg
Flurazepam30 mg at bedtime (adults and adolescents 15 years and older)15 to 30 mg at bedtime15 mg at bedtime30 mg
Lorazepam2 mg at bedtime (adults and children 12 years and older)2 to 4 mg at bedtime1 mg at bedtime

unspecified

Quazepam7.5 to 15 mg at bedtime (adults)7.5 to 15 mg at bedtime7.5 mg at bedtime15 mg
Temazepam7.5 to 15 mg at bedtime (adults)7.5 to 30 mg at bedtime15 mg at bedtime15 mg
Triazolam0.125 to 0.25 mg at bedtime (adults)0.125 to 0.5 mg at bedtime0.125 mg at bedtime0.25 mg

*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

  • 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.

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

CitationDesign/RegimenResults*Conclusion
Martin JL, et al. J Psychopharmacol .2007;21:774-782 [41814]Systematic review and metaanalysis of double-blind, randomized placebo-controlled studies of diazepam (12 trials), lorazepam (7 trials), or alprazolam (4 trials) vs placebo for the treatment of GAD in adults. Duration mode, 4 weeks; 1 study > 8 weeks. n = 1189, benzodiazepine; N=1137, placebo.

All-cause withdrawal: RR drug/placebo): 0.78 (95% CI, 0.62 to 1; p = 0.05)

 

Withdrawal due to lack of efficacy: RR 0.29 (95% CI, 0.18 to 0.45; p < 0.00001)

 

Withdrawal due to adverse events: RR 1.54 (95% CI, 1.17 to 2.03; p < 0.002)

 

 

Benzodiazepines are efficacious in the short-term treatment of GAD in clinical trials (as measured by relative risk of withdrawal due to lack of efficacy), but the evidence for effectiveness (as measured by all-cause withdrawal rates) is weaker

 

Comparison between benzodiazepines not meaningful due to study heterogeneity

Moylan S, et al. J Clin Psychopharmacol. 2011;31:647-652 [48980]Meta-analysis of single- or double-blind, randomized controlled studies of alprazolam vs another benzodiazepine for treatment of panic disorder (DSM-III or DSM-IV) in adults. A total of 8 trials included, n = 631.

Mean change in panic attack frequency/week(alprazolam - comparator): 0.6 (95% CI, 0.3 to 1.6)

 

Mean change in HAM-A (alprazolam - comparator): 0.8 points (95% CI, 0.5 to 2.1)

 

Proportion of panic attack-free patients (pooled relative risk, alprazolam vs comparator): 1.1 (95% CI, 0.9 to 1.4)

The evidence indicates that alprazolam is not superior to other benzodiazepines for the treatment of panic disorder
Amato L, et al. Cochrane Database Syst Rev. 2010(3):CD005063 [48983]Meta-analysis of randomized controlled trials evaluating benzodiazepines in comparison with placebo, another benzodiazepine, or other drugs in the treatment of alcohol withdrawal. Total of 64 studies, n = 4,309.

Seizures

Benzodiazepine vs placebo, RR = 0.16 (95% CI, 0.04 to 0.69; p = 0.01)

Benzodiazepine vs other drug, RR = 0.52 (95% CI, 0.21 to 1.31)

 

AEs

Benzodiazepine vs other drug, RR = 1.31 (95% CI, 0.99 to 1.72)

 

Dropouts

Benzodiazepine vs other drug, RR = 0.93 (95% CI, 0.70 to 1.24)

 

All comparisons of one benzodiazepine to another on all outcome measures were nonsignificant

Benzodiazepine treatment of alcohol withdrawal is highly effective in preventing seizures (vs placebo) and is equivalent to other drugs for most outcome measures; no significant differences noted between benzodiazepines
Appleton R, et al. Cochrane Database Syst Rev. 2008(3):CD001905 [20445]Systematic review of studies of treatment of tonic-clonic convulsions and status epilepticus in children; only 4 studies met inclusion criteria, only 1 compared IV diazepam with IV lorazepam.

Seizure cessation, IV lorazepam vs IV diazepam: RR = 1.09 (95% CI, 0.77 to 1.54)

 

Seizure recurrence, IV lorazepam vs IV diazepam: RR = 0.63 (95% CI, 0.27 to 1.46)

 

Respiratory depression, IV lorazepam vs IV diazepam: RR = 0.18 (95% CI, 0.02 to 1.37)

 

IV lorazepam is equivalent in efficacy and appears to produce less respiratory depression than IV diazepam for the treatment of acute tonic-clonic convulsions/status epilepticus in children
McMullan J, et al. Acad Emerg Med.2010;17:575-582 [48984]Meta-analysis studies comparing non-IV midazolam with diazepam (IV or non-IV) in treatment of status epilepticus in children and young adults. Six studies included, n = 774.

Seizure cessation failure, diazepam (any route) vs midazolam (any route): RR 1.52 (95% CI, 1.27 to 1.82; p < 0.00001)

 

Time to seizure cessation, mean difference,IV diazepam vs non-IV midazolam: 0.68 minutes (95% CI, -0.03 to 1.39)

 

Respiratory complicationsdiazepam (any route) vs midazolam (any route): RR 1.49; 95% CI, 0.25 to 8.72)

Non-IV midazolam is at least as safe and effective as non-IV or IV diazepam for the treatment of status epilepticus in children

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

*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. 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]

Neuropsychiatric adverse effects

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]

Falls

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. In general, all benzodiazepines increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. The Beers Panel specifically recommends avoiding benzodiazepines in geriatric patients with delirium, dementia, and history of falls/fractures. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). OBRA provides anxiolytic and sedative dosing guidance for benzodiazepines. When a benzodiazepine 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 in accordance with OBRA guidelines.[50840][60742][63923]

Dependence

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 syndrome

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]

Drug Interactions

CNS depressants, including Alcohol and Opioids

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]

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 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

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]

Safety Issues

History of substance abuse

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

Pulmonary disease

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]

Pregnancy

Benzodiazepines may cause fetal harm when administered to a pregnant woman. In general, benzodiazepine use for the treatment of insomnia is contraindicated for use 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 and the patient is fully informed of the potential risks to the fetus. An increased risk of congenital malformations and other developmental abnormalities is associated with benzodiazepine use during the first trimester. Transplacental distribution has resulted in neonatal effects at delivery; neonates may experience a neonatal abstinence syndrome or symptoms suggestive of floppy infant syndrome if the mother has been using benzodiazepines during the third trimester. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting.[28712][41538][62732]

Breastfeeding

Many benzodiazepines distribute into breast milk, leading to potential 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, is contraindicated in breast-feeding mothers. However, if short-term or occasional maternal therapy with a benzodiazepine is required, lorazepam or oxazepam may be reasonable alternatives for some patients. Some experts have concluded that occasional maternal treatment with usual doses of lorazepam or oxazepam would pose little risk to a nursing infant. Breastfed infants of mothers taking benzodiazepines should be frequently monitored for symptoms of overexposure including lethargy, somnolence, and poor sucking reflex. A single dose of a benzodiazepine, such as for acute treatment or a procedural purpose, does not appear to require any limitation on breastfeeding.[46105][46341][61269]

Geriatric patients

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. In general, all benzodiazepines increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. The Beers panel also recommends avoidance in geriatric patients with delirium, dementia, or a history of falls or fractures. Geriatric adults may have a decreased elimination of benzodiazepines by 50% or more, which may intensify or prolong the actions and adverse effects of the drug (e.g., sedation, ataxia). Older adults may also have conditions that make the use of benzodiazepines inherently risky (e.g., dementia). Polypharmacy in this population may increase the likelihood of drug interactions and adverse events. If a benzodiazepine must be used, then lower dosages and close monitoring are recommended. Lorazepam or oxazepam may be preferred for use in the elderly 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 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.[50832][61149][63272]

[20445]Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2008:CD001905

[28040]Xanax (alprazolam tablet) package insert. New York, NY: Pharmacia & Upjohn Company; 2021 Mar.

[28444]Klonopin® (clonazepam) package insert. Nutley, NJ: Roche Laboratories, Inc; 2016 Mar.

[28712]Valium (diazepam) tablet package insert. Little Falls, NJ: Roche Laboratories, Inc.; 2021 Feb.

[30723]Stoehr GP, Kroboth PD, Juhl RP, et al. Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics. Clin Pharmacol Ther. 1984;36:683-90.

[30935]Ozdemir M, Aktan Y, Boydag BS, et al. Interaction between grapefruit juice and diazepam in humans. Eur J Drug Metab Pharmacokinet. 1998;23:55-9.

[41506]Wolkove N, Elkholy O, Baltzan M, et al. Sleep and aging: management of sleep disorders in older people. CMAJ 2007;176:1449-54.

[41538]Xanax XR (alprazolam extended-release tablet) package insert. New York, NY: Pharmacia & Upjohn Company; 2021 Mar.

[41543]Halcion (triazolam) package insert. New York, NY: Pharmacia and Upjohn Company; 2021 Feb.

[41814]Martin JL, Sainz-Pardo M, Furukawa TA, et al. Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes based on a systematic review and meta-anaysis of clinical trials. J Psychopharmacol. 2007;21:774-82

[44717]Midazolam oral syrup package insert. Miami, FL: Atlantic Biologicals Corporation; 2021 Feb.

[46105]Summerfield RJ, Nielsen MS. Excretion of lorazepam into breast milk. Br J Anaesth 1985;57:1042-3.

[46341]National Institutes of Health (NIH). Oxazepam monograph. LactMed: Drug and Lactation Database. Available at http://http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~33rpgw:1. Accessed October 20, 2011.

[46370]Onfi (clobazam tablets) package insert. Deerfield, IL: Lundbeck Inc.; 2021 Feb.

[48980]Moylan S, Staples J, Ward SA, et al. The efficacy and safety of alprazolam versus other benzodiazepines in the treatment of panic disorder. J Clin Psychopharmacol. 2011;31:647-52.

[48983]Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010;3:CD005063.

[48984]McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med. 2010;17:575-82

[50542]Koen N, Stein DJ. Pharmacotherapy of anxiety disorders: a critical review. Dialogues Clin Neurosci 2011;13:423-437.

[50550]Reinhold JA, Mandos LA, Rickels K, et al. Pharmacological treatment of generalized anxiety disorder. Expert Opin Pharmacother 2011;12:2457-67.

[50824]Kasper S, Resinger E. Panic disorder: the place of benzodiazepines and selective serotonin reuptake inhibitors. Eur Neuropsychopharmacol. 2001;11(4):307-321.

[50827]Stein MB, Goin MK, Pollack MH, Roy-Byrne P, Sareen J, Simon NM, Campbell-Sills L. Practice guideline for the treatment of patients with panic disorder. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1680635. Accessed June 13, 2012.

[50828]Michelini S, Cassano GB, Frare F, Perugi G. Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders. Pharmacopsychiatry. 1996;29(4):127-134.

[50829]Ravindran LN, Stein MB. The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry. 2010;71(7):839-854.

[50830]Richey SM, Krystal AD. Pharmacological advances in the treatment of insomnia. Curr Pharm Des. 2011;17(15):1471-1475.

[50832]Connolly SD, Bernstein GA. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(2):267-283.

[50837]Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Clin Ther. 1992;14(6):978-995.

[50838]Weinbroum AA, Flaishon R, Sorkine P, Szold O, Rudick V. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf. 1997;17(3):181-196.

[50840]Huang AR, Mallet L, Rochefort CM, Eguale T, Buckeridge DL, Tamblyn R. Medication-related falls in the elderly: causative factors and preventive strategies. Drugs Aging. 2012;29(5):359-376.

[53391]Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? CMAJ. 2013;18:309-316. Epub 2012 Nov 26.

[56579]Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Updated Mar 10, 2020. Retrieved from the World Wide Web at www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm

[60742]Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.

[61143]Food and Drug Administration (FDA). FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm. Retrieved August 31, 2016.

[61149]Mindell JA, Emslie G, Blumer J, et al. Pharmacologic management of insomnia in children and adolescents: consensus statement. Pediatrics. 2006;117:e1223-e1232.

[61269]Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfeeding: a review of the evidence. Pediatrics 2009;124:547-56.

[61569]Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society. Epilepsy Currents 2016;16:48-61.

[62207]Sateia MJ; Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2017;13:307-349.

[62732]Payne JL. Psychopharmacology in Pregnancy and Breastfeeding. Med Clin North Am. 2019;10:629-650. Review.

[62827]Chan LN, Anderson GD. Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol). Clin Pharmacokinet. 2014;53:1115-1136.

[63262]Schutte-Rodin S, Broch L, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2017; 13(2): 307-349.

[63272]Owens JA and Moturi S. Pharmacologic treatment of pediatric insomnia. Child Adolesc Psychiatric Clin N Am. 2009; 18(4):1001-16.

[63923]The American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2019;00:1-21.

[65276]Zorumski CF, Isenberg KE. Insights into the structure and function of GABA-benzodiazepine receptors: ion channels and psychiatry. Am J Psychiatry 1991;148:162-73.

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