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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.
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.
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.
Comparison of Benzodiazepine Pharmacology
*Pro-drug which is converted to an active moiety
Comparative Dosing for Anxiety
0.25 to 0.5 mg 3 times/day (adults)
(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)
0.25 mg 2 times/day (adults)
15 mg 2 times/day (adults)
(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)
(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)
(adults and adolescents 13 years and older)
Seizure Disorders in Pediatric Patients
Seizure Disorders in Adult Patients
Comparative Dosing for Insomnia
*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.
Comparative Efficacy Trials
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
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)
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)
Benzodiazepine vs. other drug, RR = 1.31 (95% CI, 0.99 to 1.72)
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
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)
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)
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Benzodiazepines are relatively contraindicated in patients with a history of substance abuse due to the increased risk of addiction and abuse/misuse.
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.
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. 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. At this time, there is no clear evidence that exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation or floppy infant syndrome (neonatal respiratory depression, lethargy, hypotonia) and/or neonatal withdrawal symptoms. Clinical manifestations of neonatal abstinence syndrome or withdrawal may include hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties.
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.
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.
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.
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
Xanax (alprazolam tablet) package insert. New York, NY: Pharmacia & Upjohn Company; 2021 Mar.
Klonopin® (clonazepam) package insert. Nutley, NJ: Roche Laboratories, Inc; 2016 Mar.
Valium (diazepam) tablet package insert. Little Falls, NJ: Roche Laboratories, Inc.; 2021 Feb.
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.
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.
Wolkove N, Elkholy O, Baltzan M, et al. Sleep and aging: management of sleep disorders in older people. CMAJ 2007;176:1449-54.
Xanax XR (alprazolam extended-release tablet) package insert. New York, NY: Pharmacia & Upjohn Company; 2021 Mar.
Halcion (triazolam) package insert. New York, NY: Pharmacia and Upjohn Company; 2021 Nov.
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
Midazolam oral syrup package insert. Miami, FL: Atlantic Biologicals Corporation; 2021 Feb.
Summerfield RJ, Nielsen MS. Excretion of lorazepam into breast milk. Br J Anaesth 1985;57:1042-3.
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.
Onfi (clobazam tablets) package insert. Deerfield, IL: Lundbeck Inc.; 2021 Feb.
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.
Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010;3:CD005063.
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
Koen N, Stein DJ. Pharmacotherapy of anxiety disorders: a critical review. Dialogues Clin Neurosci 2011;13:423-437.
Reinhold JA, Mandos LA, Rickels K, et al. Pharmacological treatment of generalized anxiety disorder. Expert Opin Pharmacother 2011;12:2457-67.
Kasper S, Resinger E. Panic disorder: the place of benzodiazepines and selective serotonin reuptake inhibitors. Eur Neuropsychopharmacol. 2001;11(4):307-321.
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§ionid=1680635. Accessed June 13, 2012.
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.
Ravindran LN, Stein MB. The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry. 2010;71(7):839-854.
Richey SM, Krystal AD. Pharmacological advances in the treatment of insomnia. Curr Pharm Des. 2011;17(15):1471-1475.
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.
Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Clin Ther. 1992;14(6):978-995.
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.
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.
Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? CMAJ. 2013;18:309-316. Epub 2012 Nov 26.
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
Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
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.
Mindell JA, Emslie G, Blumer J, et al. Pharmacologic management of insomnia in children and adolescents: consensus statement. Pediatrics. 2006;117:e1223-e1232.
Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfeeding: a review of the evidence. Pediatrics 2009;124:547-56.
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.
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.
Payne JL. Psychopharmacology in Pregnancy and Breastfeeding. Med Clin North Am. 2019;10:629-650. Review.
Chan LN, Anderson GD. Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol). Clin Pharmacokinet. 2014;53:1115-1136.
Owens JA and Moturi S. Pharmacologic treatment of pediatric insomnia. Child Adolesc Psychiatric Clin N Am. 2009; 18(4):1001-16.
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.
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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