Benzodiazepines …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.10.2021
Released 02.23.1999
Expires For CME 03.10.2024

Benzodiazepines

Author: K K Jain MD†

See Contributor Disclosures

Benzodiazepines

In This Article

Quick Link

Introduction

Overview

Benzodiazepines are psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The pharmacological target of benzodiazepines is GABA, the major inhibitory neurotransmitter in the central nervous system. The best-known drug of this series is diazepam, which is used as an anxiolytic, sedative-hypnotic, and anticonvulsant. Midazolam is used for preoperative sedation/anxiolysis with anterograde amnesia. Adverse effects include drowsiness and potential for addiction.

Key points

	• Benzodiazepines have a better safety profile than barbiturates but are potentially addictive.
	• Diazepam has been in clinical use for over half a century as an anxiolytic and antiepileptic agent.
	• Midazolam is more potent than diazepam and is used to induce preoperative sedation/anxiolysis with anterograde amnesia.
	• Nonbenzodiazepine agents are now preferred as hypnotic agents.

Historical note and terminology

Benzodiazepines are psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first benzodiazepine, chlordiazepoxide (Librium), was discovered in 1955 and became available for clinical use in 1960 (33). Diazepam, the best-known benzodiazepine, was developed in the late 1950s and has been marketed as Valium since 1963. It was approved by the Food and Drug Administration in the United States prior to 1982 and is still 1 of the top 200 drugs. Although originally intended as an anxiolytic, it now has many other indications. Intravenous diazepam has been used since the 1960s for controlling status epilepticus (24). It is available in oral as well as parenteral forms, and a rectal gel was introduced in 1997.

Currently, there are approximately 35 benzodiazepine derivatives, 21 of which have been approved internationally. For more information, visit www.emcdda.europa.eu/publications/drug-profiles/benzodiazepine.

A classification of benzodiazepines into various types based on chemical structure is as follows:

	• 2-keto compounds: chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, and others.
	• 3-hydroxy compounds: lorazepam, lormetazepam, oxazepam, temazepam.
	• 7-nitro compounds: clonazepam, flunitrazepam, nimetazepam, nitrazepam.
	• Triazolo compounds: adinazolam, alprazolam, estazolam, triazolam.
	• Imidazo compounds: climazolam, loprazolam, midazolam.

After half a century of use, considerable information has accumulated about applications of benzodiazepines in neuropsychiatric disorders, other diseases, and anesthesia (07). Although some of their uses were empirical, benzodiazepines had a better safety profile than barbiturates. Now there is increasing awareness of the adverse effects of benzodiazepines, particularly addiction and drug abuse. Nevertheless, benzodiazepines are frequently prescriptions for short-term anxiety relief and some neurologic disorders. Benzodiazepines are now less popular than nonbenzodiazepines for treatment of insomnia. Nonbenzodiazepine hypnotics, which include zolpidem, zaleplon, and eszopiclone, have different molecular structures, but they act on the same benzodiazepine receptors and produce similar sedative effects.

This article will briefly review the clinical pharmacology of benzodiazepines, with a focus on diazepam, the most widely used benzodiazepine, as an example. Midazolam (Versed) will also be described.

Pharmacology

The pharmacological target of benzodiazepines is GABA, the major inhibitory neurotransmitter in the central nervous system. Benzodiazepine binding sites are contained within GABA_A receptor complex in central nervous system neurons. The greater affinity of GABA_A receptor for GABA increases the frequency of chloride-channel opening and potentiates the inhibitory effect of GABA in the central nervous system.

Pharmacological effects of classic benzodiazepines in the central nervous system vary according to the receptor subtype they bind with (26):

	• alpha1beta gamma2 receptors in the cerebral cortex, substantia nigra pars reticulata, hippocampus and cerebellum to produce sedation, anterograde amnesia, anticonvulsive activity, and muscle relaxation.
	• alpha2beta gamma2 receptors in the cerebral cortex and hippocampus to produce anxiolysis and muscle relaxation.
	• alpha3beta gamma2 receptors in the temporal neocortex, motor cortex, substantia nigra, and hippocampus to produce anxiolysis and muscle relaxation.
	• alpha5beta gamma2 receptors in the motor cortex and hippocampus to produce memory impairment and muscle relaxation.

The intensity of affinity for receptors varies among different benzodiazepines. Midazolam has twice the affinity for benzodiazepine receptors that diazepam has. It binds to GABA receptors at several sites within the CNS, including the limbic system and reticular formation. By increasing the neuronal membrane permeability to chloride ions, it enhances the inhibitory effects of GABA, and the shift in chloride ions causes hyperpolarization as well as stabilization of the neuronal membrane. Duration of anterograde amnesia following intramuscular injection is 1 hour and 20 to 40 minutes following intravenous injection. Sedative effects of oral midazolam and oral diazepam are comparable, but intravenous midazolam produces more sedation whereas anxiolysis is more in both the midazolam groups than the diazepam group (39).

Pharmacodynamics. Diazepam induces a calming effect, presumably by acting on parts of the limbic system, the thalamus, and the hypothalamus. Unlike chlorpromazine and reserpine, it has no demonstrable peripheral autonomic blocking action. Therapeutic effects of nonsedating doses of diazepam in clinical anxiety are based on its modulation of attentional vigilance and reduction of startle responsivity (21). Antiseizure effects of diazepam and midazolam are approximately equal.

Pharmacokinetics. Pharmacokinetics of diazepam vary according to the galenic form of the drug: tablets, slow-release capsules, or injection.

Tablets. The important features are:

	• Diazepam is lipid soluble and is rapidly absorbed after oral administration.
	• The half-life varies from 20 to 70 hours.
	• It is highly protein bound (98%).
	• Diazepam is metabolized to desmethyldiazepam (half-life 36 to 96 hours) and further to oxazepam, which is the active metabolite.
	• Oxazepam is conjugated to an inactive metabolite that is excreted in the urine.

Slow-release formulation. Important features of this form are:

	• The mean time to maximum plasma diazepam concentrations after administration of 15 mg diazepam slow-release capsules is 5.3 hours.
	• The mean half-life is 36 hours.
	• The range of average, minimum, steady-state plasma diazepam concentrations during once-daily administration of 15 mg diazepam slow-release capsules is 196 to 341 ng/mL.
	• The administration of one 15 mg diazepam slow-release capsule results in blood levels of diazepam over a 24-hour period, comparable to those of 5 mg diazepam tablets given 3 times daily.

Pharmacokinetics of midazolam. Important features are:

	• Bioavailability is 40% to 50% following oral administration and 90% following intramuscular injection.
	• Peak plasma concentration is 90 ng/mL following intramuscular injection.
	• Half-life is 2 to 6 hours
	• 97% of the drug is protein-bound.
	• Midazolam is metabolized by the liver via CYP3A4 to metabolite 1-hydroxymethylmidazolam.

Because it is water soluble, midazolam takes approximately 3 times longer than diazepam as a preoperative sedative. Therefore, waiting for 2 to 3 minutes is required to fully evaluate sedative effects before initiating the procedure or repeating dose.

Routes of delivery of benzodiazepines. Although most of the benzodiazepines are given orally, intravenous, rectal, and nasal routes are also used.

Intravenous. Following a bolus intravenous administration, diazepam enters the brain rapidly and is redistributed into the peripheral tissues, providing a central nervous system depressive effect for less than 2 hours.

Rectal. The absorption is rapid and consistent. The rectal drug-delivery system offers an easy, safe, and bioavailable method.

Intranasal. Intranasal administration of benzodiazepines is suitable for rapid delivery, but the pharmacokinetic properties differ between the intranasal, oral, and intravenous formulations. Intranasal benzodiazepines have an overall Tmax that varies between 10 and 25 minutes, and bioavailability is between 38% and 98% (36). Diazepam is rapidly absorbed following intranasal administration in healthy human volunteers and has a longer half-life, which may result in an extended duration of action. An open-label study has shown that diazepam can be delivered by nasal spray to achieve effective therapeutic concentrations during the convulsive phase of tonic-clonic seizures (32).

Pharmacogenetics. CYP2C9, an enzyme from the family of cytochrome 450, metabolizes benzodiazepines. Polymorphisms of the enzyme can predispose an individual to toxicity of benzodiazepines. The polymorphisms can be identified by genetic testing.

Indications

Indications for the use of benzodiazepines, mostly diazepam, include the following:

	• Short-term relief of the symptoms of anxiety.
	• Benzodiazepines show a beneficial effect for the management of alcohol withdrawal symptoms, particularly, seizures.
	• Diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), and athetosis. Diazepam has been reported to be an effective medication for hemidystonia following stroke.
	• Diazepam by injection is used as an adjunct prior to endoscopic procedures and surgery if apprehension, anxiety, or acute stress reactions are present, and to diminish the patient's recall of the procedures.
	• Administration of benzodiazepines is well established in status epilepticus, but intermittent benzodiazepine use in the treatment of chronic epilepsy is little known beyond catamenial epilepsy. In the past, intravenous diazepam has been used for the control of status epilepticus. Lorazepam is at least as effective as intravenous diazepam and is associated with fewer adverse events in the treatment of acute tonic-clonic convulsions.
	• Rectal diazepam can be used for management of acute repetitive seizures in both children and adults. Diazepam rectal gel is approved by the FDA for the management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs, who require intermittent use of diazepam to control bouts of increased seizure activity. Chronic administration of diazepam rectal gel is not recommended as it may cause tachyphylaxis.
	• Intravenous diazepam has been used in the treatment of patients with acute neuroleptic-induced akathisia who require immediate relief.
	• Intravenous diazepam for the management of severe tetanus.
	• Intravenous diazepam is used effectively in planned intrathecal baclofen withdrawal to prevent baclofen withdrawal syndrome.
	• In critically ill adult trauma patients admitted to an intensive care unit, diazepam, at an average dosage of 40 mg/d, appears to be safe and effective in providing adequate sedation (14).
	• Midazolam is used for preoperative sedation/anxiolysis with anterograde amnesia.
	• A metaanalysis of studies of use of benzodiazepines for insomnia in patients with chronic obstructive pulmonary disease indicates that they are efficient and safe hypnotics. Compared with placebo, benzodiazepines partly improved sleep quality, and, excepting an increase in maximum transcutaneous carbon dioxide pressure during sleep, there were no significant effects on pulmonary function (19).

Off-label uses

	• Intravenous midazolam has been used for control of refractory status epilepticus.
	• No adequately controlled trials support the use of benzodiazepines in the treatment of non-alcohol withdrawal-related delirium among hospitalized patients.
	• Results of a randomized, double-blind phase 1 trial on healthy male volunteers are suggestive of a possible anti-hyperalgesic effect of benzodiazepines acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain (38).
	• Social anxiety disorder (29)
	• A double-blind, randomized clinical trial has shown that in children with convulsive status epilepticus, treatment with lorazepam (not approved for this indication) did not result in improved efficacy or safety compared with diazepam, which is an approved drug for this indication (06).
	• A systematic review of randomized trials that evaluated benzodiazepines in comparison with placebo or antipsychotics, and as adjuncts to antipsychotics, has revealed conflicting results leading to the recommendation that use of these drugs in clinical practice and antipsychotic trials should be limited (30). Long-term use of benzodiazepines is associated with impaired attention/working memory in schizophrenia, which requires regular evaluation of benefit/risk ratio. If possible, alternative pharmacological as well as nonpharmacological therapies for comorbid anxiety disorders and sleep disorders are preferred (11).
	• In 2015, the U.S. Supreme Court allowed the use of benzodiazepines, particularly midazolam, as alternative drugs in lethal injections for the death penalty because pharmaceutical manufacturers refused to provide barbiturates for execution. Midazolam can now be used in the controversial 3-drug execution protocol adopted by the state of Oklahoma since 1997, which involves the intravenous administration of the barbiturate sodium thiopental to induce unconsciousness to shield prisoners from the terror of asphyxiation, followed by a paralytic agent to inhibit musculoskeletal movements and to paralyze the diaphragm, causing asphyxiation, and, finally, infusion of potassium chloride to induce cardiac arrest.
	• Benzodiazepines are used to treat symptoms of restless legs syndrome; however, according to a review by the American Academy of Sleep Medicine, these drugs should not be used as a first-line treatment, but can be used as a co-adjuvant therapy. In the absence of adequate clinical trials, the effectiveness of benzodiazepines for the treatment of restless legs syndrome is unknown (04).
	• Oral benzodiazepine is a proposed treatment for cannabinoid hyperemesis syndrome associated with chronic cannabis use as it decreases activation of cannabinoid type 1 receptor in the frontal cortex, and its sedative effect reduces the anticipation of nausea and vomiting (17).

Special considerations

Precautions. The following precautions are important for the use of benzodiazepines:

	• Patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.
	• Patients should be advised against the simultaneous ingestion of alcohol and other central nervous system-depressant drugs during benzodiazepine therapy.
	• When using diazepam intravenously, larger veins should be used and the solution should be injected slowly, taking at least 1 minute for each 5 mg (1 mL) given. Care should be taken to avoid intraarterial administration or extravasation.
	• Injectable benzodiazepines should not be administered to patients in shock, coma, or in acute alcoholic intoxication with depression of vital signs.
	• Resuscitative equipment including that necessary to support respiration should be readily available during the use of intravenous diazepam.
	• Midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. It should be used only in settings that can provide for continuous monitoring of respiratory and cardiac function.

Pediatric. Efficacy and safety of parenteral benzodiazepines has not been established in neonates (30 days of age or younger). Benzodiazepines cause unwanted effects in neonates with immature hepatic function during a developmental period of neuroplasticity (22). Inability to biotransform diazepam into inactive metabolites may lead to prolonged central nervous system depression. Diazepam is contraindicated in children younger than 6 months of age because of lack of adequate clinical experience.

In pediatric use, the aim is to obtain maximum clinical effect with the minimum amount of diazepam and, thus, reduce the risk of hazardous side effects, such as apnea, or prolonged periods of somnolence. It is recommended that the drug be given slowly over a 3-minute period in a dosage not to exceed 0.25 mg/kg. After an interval of 15 to 30 minutes, the initial dosage can be safely repeated. If, however, relief of symptoms is not obtained after a third administration, adjunctive therapy appropriate to the condition being treated is recommended.

Geriatric. Changes in pharmacokinetics and pharmacodynamics of benzodiazepines during aging may predispose to adverse outcomes. In elderly and debilitated patients, it is recommended that the dosage of benzodiazepines be limited to the smallest effective amount to preclude the development of oversedation or gait impairment with falls. Although benzodiazepine consumption is statistically linked to falls, it is of poor predictive value because of the multifactorial nature of falls (35). Predisposition to falls varies with different benzodiazepines. Diazepam has the strongest association with falls, particularly when compared with oxazepam (01). In the case of diazepam, initial dose of 2 to 2.5 mg once or twice daily should be increased gradually as needed and tolerated. In elderly subjects chronic use of diazepam as a hypnotic agent produces an increase in nighttime heart rate and blood pressure, particularly systolic blood pressure, which is probably due to diazepam-mediated decrease in vagal tone, and is a risk factor for cardiovascular morbidity and mortality (10).

Pregnancy. An increased risk of congenital malformations associated with benzodiazepines during the first trimester of pregnancy has been suggested in several studies. Use of diazepam during this period should be avoided. There is a moderate association between exposure to benzodiazepine anxiolytics and child internalizing problems (internal distress) at the ages of 1.5 years and 3 years that are not likely due to confounding factors, whereas exposure to nonbenzodiazepine hypnotics was not associated with any adverse outcomes after adjustment (02). Injectable diazepam is not recommended for obstetrical use. An analysis of data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications has shown that infants of mothers with psychiatric disorders who were exposed to benzodiazepines during pregnancy have an increased risk of neonatal intensive care unit admissions and small head circumferences (12).

Anesthesia. Intravenous midazolam is used as an anesthetic agent for performing minor surgical procedures and endoscopy. When used with a narcotic analgesic, the dosage of the narcotic should be reduced by at least one third and administered in small increments.

Adverse effects

Prescription guidelines recommend limiting benzodiazepine treatment to only a few weeks, but long-term use of benzodiazepines is common, particularly in Europe. Studies of the association between long-term benzodiazepine use and brain abnormalities have yielded conflicting results, but they do not usually result in abnormalities that are demonstrable by brain imaging. There are several adverse effects of benzodiazepines.

Neuropsychiatric effects. Side effects commonly reported with benzodiazepine use are drowsiness, fatigue, and ataxia. Less commonly encountered are confusion, depression, dysarthria, headache, slurred speech, tremor, vertigo, and blurred vision. Falls in older adults are related to the use of benzodiazepines; therefore, these drugs should be prescribed as a short-term therapy and progressively withdrawn (08). Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, and rage reaction may also occur. These usually subside if the drug is discontinued. Capgras syndrome, the delusion that identical appearing impostors have replaced familiar people, has been reported as an adverse reaction to diazepam. A review of the literature indicates that benzodiazepines are associated with an overall increase in the risk of attempted or completed suicide, which may be due to impulsivity or aggression, rebound or withdrawal symptoms, as well as toxicity of overdose (09).

Amnesia. Amnesic states associated with the benzodiazepines are as follows:

Amnesia is a desired effect when benzodiazepines are used prior to a surgical procedure to induce anterograde amnesia, eg, midazolam. An experimental study has shown that midazolam-induced amnesia reduces memory for details and affects the event-related potentials as correlates of recollection and familiarity (23). Lorazepam is an intermediate-acting benzodiazepine used intravenously to induce preoperative anterograde amnesia. Studies in human volunteers have shown that lorazepam produces dose-related deficits in verbal secondary memory as well as impairment of information acquisition and recall. Memory impairment with lorazepam is independent of increased sedation. In contrast to deficits in episodic memory with sedatives, no lorazepam-induced impairments on tests of semantic memory have been reported.

In addition to anterograde amnesia following triazolam use, there is amnesic complex automatism, during which the subjects can perform complicated tasks without errors but have no recollection of having done so afterwards. Triazolam syndrome in the elderly is characterized by reversible delirium, anterograde amnesia, and automatic movements that are causally associated with triazolam used as a hypnotic.

Acute administration of diazepam can produce anterograde amnesia of both verbal and visual information. Intravenous diazepam impairs free recall significantly in a dose-dependent manner. Diazepam induces prospective memory impairment. Administered at therapeutic dosage, diazepam affects attentional shifting in the temporal domain and impairs dual-task performance.

A randomized, placebo-controlled study of diazepam versus tandospirone on driving performance and cognitive function in healthy volunteers showed that acute doses of diazepam significantly impaired the harsh-braking performance as compared to acute doses of tandospirone (34).

Effect on the immune system. Diazepam inhibits the immune system and should be avoided in patients with an impaired immune system. Because of its effect on the immune system, diazepam may augment severity of rare poxvirus infections such as vaccinia virus as demonstrated in rats infected with this virus (15). As vaccinia virus is still used as live vaccine against smallpox, there is also a risk of enhanced side effects or possible failure of vaccination.

Development of tolerance. Clinical use of benzodiazepines is limited by tolerance. An experimental study has shown that flurazepam exposure enhances degradation of alfa2 subunit-containing GABA A receptors after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition (16). This finding provides an insight into the initial neuroadaptive responses occurring with benzodiazepine treatment.

Ineffective benzodiazepine therapy of stiff person syndrome due to development of tolerance to the drug may lead to withdrawal syndrome with convulsions. Immunomodulatory properties of peripheral benzodiazepine receptor suggest that increased antigenic stimulation during benzodiazepine therapy and glutamatergic hyperactivity may account for convulsions (40). Management includes use of alternative muscle relaxant tizanidine, which is a glutamate release inhibitor.

Drug dependence. Benzodiazepines have the potential for habituation and dependence. Addiction-prone individuals should be under careful surveillance when receiving these drugs for prolonged periods. Benzodiazepines are often a secondary drug of abuse as benzodiazepine use disorders have been reported in a small percentage of benzodiazepine users. Benzodiazepine misuse is more common in persons with a history of a substance use disorder. This concern has led to a call for research to determine the most effective strategies to reduce the inappropriate prescription of benzodiazepines and establish safer and more effective treatment options for anxiety and insomnia (27).

Drug withdrawal. Withdrawal symptoms, such as convulsions, tremor, muscle cramps, vomiting, and sweating can occur following the abrupt discontinuance of diazepam.

Measures for the management of benzodiazepine withdrawal symptoms include the following:

	• For prevention of withdrawal symptoms, benzodiazepines should be discontinued gradually over a period of several weeks. A multicenter, 3-arm, cluster randomized, controlled trial evaluated groups that received usual care (control), structured intervention with stepped-dose reduction and follow-up visits, or structured intervention with written stepped-dose reduction (37). The interventions, compared to the control group, were effective for cessation of benzodiazepines use, and most patients who discontinued at 12 months remained abstinent at 3 years.
	• If the patient has been using several benzodiazepines, switch to the use of only one for detoxification, eg, diazepam.
	• Carbamazepine, 200 mg twice a day, can be used as concomitant pharmacotherapy for benzodiazepine withdrawal (31).
	• There is good evidence for cognitive behavioral therapy and motivational approaches in the psychotherapeutic management of patients with benzodiazepine withdrawal.

Complications of intravenous injection. Intravenous injection of large amounts of diazepam may produce hypotension and excessive sedation. Hypotension may be combated by levarterenol or metaraminol. Thrombophlebitis of the injected vein may occur.

Drowsiness. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with benzodiazepine is known or suspected. Experimental studies have shown that magnetic nanoparticles conjugated with beta-cyclodextrin have a hemoadsorbent action on diazepam, and the adsorbed diazepam can be removed from blood by an external magnetic field, indicating a potential application in treatment of diazepam overdose by hemoperfusion (03).

Adverse effects of combination of benzodiazepines with opioids in chronic pain patients. A cross-sectional study of both opioid and benzodiazepine use together in chronic pain found the anticipated negative effects of opioid medication, and particularly consistent associations between benzodiazepine use and poor outcome for mood (13). There was no evidence for any benefit of combination of these drugs. Prescription of benzodiazepines for patients with opioid dependency undergoing opioid agonist treatment may increase mortality risk (20). Prescription of benzodiazepines in chronic pain management should be restricted.

References

01: Ballokova A, Peel NM, Fialova D, Scott IA, Gray LC, Hubbard RE. Use of benzodiazepines and association with falls in older people admitted to hospital: a prospective cohort study. Drugs Aging 2014;31(4):299-310. PMID 24566878
02: Brandlistuen RE, Ystrom E, Hernandez-Diaz S, et al. Association of prenatal exposure to benzodiazepines and child internalizing problems: a sibling-controlled cohort study. PLoS One 2017;12(7):e0181042. PMID 28746341
03: Cai K, Li J, Luo Z, Hu Y, Hou Y, Ding X. β-Cyclodextrin conjugated magnetic nanoparticles for diazepam removal from blood. Chem Commun (Camb) 2011;47(27):7719-21. PMID 21755073
04: Carlos K, Prado GF, Teixeira CD, et al. Benzodiazepines for restless legs syndrome. Cochrane Database Syst Rev 2017;3:CD006939. PMID 28319266
05: Cereghino JJ, Cloyd JC, Kuzniecky RI. Rectal diazepam gel for treatment of acute repetitive seizures in adults. Arch Neurol 2002;59:1915-20. PMID 12470180
06: Chamberlain JM, Okada P, Holsti M, et al. Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA 2014;311(16):1652-60. PMID 24756515
07: Dell'osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders. A critical reappraisal. Eur Psychiatry 2013;28(1):7-20. PMID 22521806
08: Díaz-Gutiérrez MJ, Martínez-Cengotitabengoa M, Sáez de Adana E, et al. Relationship between the use of benzodiazepines and falls in older adults: a systematic review. Maturitas 2017;101:17-22. PMID 28539164
09: Dodds TJ. Prescribed benzodiazepines and suicide risk: a review of the literature. Prim Care Companion CNS Disord 2017;19(2). PMID 28257172
10: Fogari R, Costa A, Zoppi A, et al. Diazepam as an oral hypnotic increases nocturnal blood pressure in the elderly. Aging Clin Exp Res 2019;31(4):463-8.** PMID 29959667
11: Fond G, Berna F, Boyer L, et al. Benzodiazepine long-term administration is associated with impaired attention/working memory in schizophrenia: results from the national multicentre FACE-SZ data set. Eur Arch Psychiatry Clin Neurosci 2018;268(1):17-26.** PMID 28349247
12: Freeman MP, Góez-Mogollón L, McInerney KA, et al. Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: results from a prospective registry of women with psychiatric disorders. Gen Hosp Psychiatry 2018;53:73-9. PMID 29958100
13: Gauntlett-Gilbert J, Gavriloff D, Brook P. Benzodiazepines may be worse than opioids: negative medication effects in severe chronic pain. Clin J Pain 2016;32(4):285-91. PMID 25968447
14: Gesin G, Kane-Gill SL, Dasta JF, Birrer KL, Kolnik LJ, Cheatham ML. Diazepam as a component of goal-directed sedation in critically ill trauma patients. J Crit Care 2011;26(2):122-6. PMID 21106343
15: Huemer HP, Lassnig C, Nowotny N, Irschick EU, Kitchen M, Pavlic M. Diazepam leads to enhanced severity of orthopoxvirus infection and immune suppression. Vaccine 2010;28(38):6152-8. PMID 20659521
16: Jacob TC, Michels G, Silayeva L, Haydon J, Succol F, Moss SJ. Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition. Proc Natl Acad Sci U S A 2012;109(45):18595-600. PMID 23091016
17: Kheifets M, Karniel E, Landa D, Vons SA, Meridor K, Charach G. Resolution of cannabinoid hyperemesis syndrome with benzodiazepines: a case series. Isr Med Assoc J 2019;21(6):404-7.** PMID 31280510
18: Kriegel DL 2nd, Azrak A. Benzodiazepines for panic disorder in adults. Am Fam Physician 2020;101(7):Online. PMID 32227829
19: Lu XM, Zhu JP, Zhou XM. The effect of benzodiazepines on insomnia in patients with chronic obstructive pulmonary disease: a meta-analysis of treatment efficacy and safety. Int J Chron Obstruct Pulmon Dis 2016;11:675-85. PMID 27110106
20: Macleod J, Steer C, Tilling K, et al. Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records. PLoS Med 2019;16(11):e1002965. PMID 31770388
21: Murphy SE, Downham C, Cowen PJ, Harmer CJ. Direct effects of diazepam on emotional processing in healthy volunteers. Psychopharmacology (Berl) 2008;199(4):503-13. PMID 18581100
22: Nelson MA, Bradshaw WT. Use of benzodiazepines as anxiolytics in neonates: are we there yet? Adv Neonatal Care 2014;14(2):78-85.** PMID 24675625
23: Nyhus E, Curran T. Midazolam-induced amnesia reduces memory for details and affects the ERP correlates of recollection and familiarity. J Cogn Neurosci 2012;24(2):416-27. PMID 22004049
24: Otto JL, Schlagenhauf G. The use of diazepam in the control of status epilepticus. Electroencephalogr Clin Neurophysiol 1968;24:398. PMID 4174050
25: Rao SK, Mahulikar A, Ibrahim M, Shah A, Seraji-Bozorgzad N, Mohamed W. Inadequate benzodiazepine dosing may result in progression to refractory and non-convulsive status epilepticus. Epileptic Disord 2018;20(4):265-9. PMID 30113012
26: Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT. Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. Pharmacol Rev 2011;63(1):243-67. PMID 21245208
27: Schmitz A. Benzodiazepines: the time for systematic change is now. Addiction 2021;116(2):219-21.** PMID 32335948
28: Silbergleit R, Lowenstein D, Durkalski V, Conwit R; NETT Investigators. Lessons from the RAMPART study--and which is the best route of administration of benzodiazepines in status epilepticus. Epilepsia 2013;54 Suppl 6:74-7. PMID 24001080
29: Silberman EK. The role of benzodiazepines in treating social anxiety disorder. Am J Psychiatry 2014;171(7):795. PMID 24980174
30: Sim F, Sweetman I, Kapur S, Patel MX. Re-examining the role of benzodiazepines in the treatment of schizophrenia: a systematic review. J Psychopharmacol 2015;29(2):212-23. PMID 25049261
31: Soyka M. Treatment of benzodiazepine dependence. N Engl J Med 2017;376:1147-57.
32: Sperling MR, Haas KF, Krauss G, et al. Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy. Epilepsia 2014;55(10):1544-50. PMID 25154625
33: Sternbach LH. The discovery of librium. Agents Actions 1972;2(4):193-6. PMID 4557348
34: Takahashi M, Iwamoto K, Kawamura Y, et al. The effects of acute treatment with tandospirone, diazepam, and placebo on driving performance and cognitive function in healthy volunteers. Hum Psychopharmacol 2010;25(3):260-7. PMID 20373478
35: Uhart M, Odouard E, Carlier C, Maire P, Ducher M, Bourguignon L. Relationship between benzodiazepines use and falls in the elderly: a multicenter study in three geriatric centers of a university hospital. Ann Pharm Fr 2012;70(1):46-52. PMID 22341008
36: Veldhorst-Janssen NM, Fiddelers AA, van der Kuy PH, Neef C, Marcus MA. A review of the clinical pharmacokinetics of opioids, benzodiazepines, and antimigraine drugs delivered intranasally. Clin Ther 2009;31(12):2954-87. PMID 20110035
37: Vicens C, Sempere E, Bejarano F, et al. Efficacy of two interventions on the discontinuation of benzodiazepines in long-term users: 36-month follow-up of a cluster randomised trial in primary care. Br J Gen Pract 2016;66(643):e85-91. PMID 26823269
38: Vuilleumier PH, Besson M, Desmeules J, Arendt-Nielsen L, Curatolo M. Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study. PLoS One 2013;8(3):e43896. PMID 23554851
39: Tyagi P, Dixit U, Tyagi S, Jain A. Sedative effects of oral midazolam, intravenous midazolam and oral diazepam. J Clin Pediatr Dent 2012;36(4):383-8. PMID 23019837
40: Zdziarski P. A case of stiff person syndrome: immunomodulatory effect of benzodiazepines: successful rituximab and tizanidine therapy. Medicine (Baltimore) 2015;94(23):e954. PMID 26061327

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Benzodiazepines

Other Pertinent Drugs

Non-benzodiazepine hypnotics
Barbiturates
Tizanidine

Also Relevant

Absence status epilepticus
Drug-induced delirium
Drug-induced memory disturbance
Drug-induced seizures
Epilepsy
- Febrile seizures
- Illicit drug use: neurologic complications
- Pharmacological treatment of insomnia
- Restless legs syndrome
- Status migrainosus
- Stiff-person syndrome
- Tetanus
- Tizanidine
- Tonic status epilepticus

	• Patients with a known hypersensitivity to benzodiazepines
	• Acute narrow angle glaucoma
	• Myasthenia gravis
	• Spinal and cerebellar ataxia
	• Sleep apnea syndrome and chronic respiratory insufficiency
	• Acute CNS-depressant intoxication

	• The clearance of benzodiazepines can be delayed in association with cimetidine administration.
	• The central nervous system depressive effect of benzodiazepines is aggravated by concomitant use of phenothiazines, narcotics, barbiturates, monoamine oxidase inhibitors, and tricyclic antidepressants.
	• Interactions of benzodiazepines with selective serotonin reuptake inhibitors are variable. Fluoxetine increases the plasma concentrations of diazepam by inhibiting CYP2C19. The potential for interaction is less for sertraline. Paroxetine and citalopram are unlikely to cause interactions with diazepam.
	• Phenytoin toxicity may occur with concurrent benzodiazepine therapy because phenytoin is a known inducer of drugs metabolized by enzymes CYP2C, CYP2D, and CYP3A. Moreover, the metabolism of phenytoin may be altered by drugs influencing these enzymes, such as benzodiazepines.

Benzodiazepines …

Benzodiazepines

Introduction

Overview

Key points

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Telehealth and cognitive behavioral therapy for insomnia (CBT-I)

NonREM parasomnias

Toxic and nutritional deficiency optic neuropathies

Nystagmus

Third nerve palsy

	• The usual dose of diazepam for anxiety or muscle spasms is 1 or 2 slow-release capsules (15 to 30 mg) once daily.
	• Intravenous diazepam dosage should be individualized for maximum beneficial effect. The usual recommended dose in older children and adults ranges from 2 to 20 mg, depending on the indication and its severity. In acute conditions the injection may be repeated within 1 hour although an interval of 3 to 4 hours is usually satisfactory.

Benzodiazepines

Introduction

Overview

Key points

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Telehealth and cognitive behavioral therapy for insomnia (CBT-I)

NonREM parasomnias

Toxic and nutritional deficiency optic neuropathies

Nystagmus

Third nerve palsy

This is an article preview.
Start a Free Account
to access the full version.