Understanding the Benzo Effect: A Comprehensive Guide to Benzodiazepines

Benzodiazepines are a class of medications that act on benzodiazepine receptors within the central nervous system. These drugs, including alprazolam, clonazepam, and diazepam, are FDA-approved and play a vital role in managing various conditions, notably seizure activity, which accounts for a significant portion of emergency department visits in the United States. Beyond seizure control, benzodiazepines are prescribed for insomnia, acute status epilepticus, amnesia induction, agitation, anxiety, spastic conditions, and seizure disorders. A deep understanding of benzodiazepine pharmacology is essential for healthcare professionals to create tailored treatment plans, optimize dosages, and minimize potential adverse effects, ensuring patient safety and efficacy. This article provides a thorough exploration of benzodiazepines, covering their indications, mechanism of action, safe administration, potential adverse effects, contraindications, toxicology, and necessary monitoring in clinical settings. Furthermore, it emphasizes the crucial role of a collaborative interprofessional healthcare team in optimizing benzodiazepine therapy and delivering patient-centered care.

Indications for Benzodiazepine Use

Benzodiazepines exert their therapeutic effects by interacting with benzodiazepine receptors in the central nervous system (CNS). Their effectiveness in ceasing seizure activity is well-established, addressing a significant percentage of emergency department visits annually in the US. The clinical applications of benzodiazepines are broad, encompassing the management of insomnia, acute status epilepticus, procedural amnesia, agitation, anxiety disorders, spasticity, and various seizure disorders. Psychiatry frequently utilizes benzodiazepines off-label to address conditions such as Tourette syndrome, delirium, delirium tremens, sleep disturbances, and medication-induced movement disorders like tremors, tics, tardive dyskinesia, and chorea.

FDA-Approved Benzodiazepine Indications

The Food and Drug Administration (FDA) has approved several benzodiazepines for specific therapeutic uses, primarily focusing on anxiety, seizure management, and alcohol withdrawal.

• Chlordiazepoxide: This benzodiazepine is mainly indicated for managing alcohol withdrawal syndrome.

• Clonazepam: Clonazepam is approved for the treatment of panic disorder and agoraphobia. It is also effective in managing certain seizure types, including myoclonic and absence seizures.

• Diazepam: Diazepam is utilized in the management of alcohol withdrawal. Rectal diazepam is specifically indicated for treating febrile seizures, particularly in pediatric populations.

• Flurazepam: Flurazepam is indicated for the treatment of insomnia, helping patients achieve and maintain sleep.

• Midazolam: Midazolam is approved for managing convulsive status epilepticus and for procedural sedation. In critical care settings like MICUs/SICUs, midazolam is used for sedation in mechanically ventilated patients.

• Quazepam: The American College of Physicians recommends quazepam primarily for treating chronic insomnia in adult patients.

• Triazolam: Triazolam is mainly indicated for sleep-onset insomnia, helping individuals fall asleep faster.

• Remimazolam: Approved by the FDA in 2020, remimazolam is indicated for short-duration procedures requiring sedation.

Mechanism of Action: How Benzodiazepines Work

Benzodiazepines’ therapeutic action stems from their interaction with benzodiazepine receptors in the CNS. These receptors are integral parts of the gamma-aminobutyric acid type A (GABA-A) receptor, a protein complex forming a chloride channel within neurons. The GABA-A receptor is composed of five transmembrane subunits: two alpha, two beta, and one gamma subunit. GABA, an inhibitory neurotransmitter, binds to receptor sites located on the extracellular portions of the alpha and beta subunits. Benzodiazepines, in turn, bind to a distinct site formed by the extracellular portions of the alpha and gamma subunits.

Upon benzodiazepine binding, a conformational change occurs in the central pore of the GABA-A receptor, facilitating the influx of chloride ions into the neuron. This chloride influx leads to neuronal hyperpolarization, effectively causing CNS depression and mediating the therapeutic “Benzo Effect”. Benzodiazepines enhance the frequency of GABA-A receptor chloride channel opening in the presence of GABA. Crucially, benzodiazepines have no effect on GABA-A receptor function in the absence of GABA, highlighting their modulatory rather than direct agonist activity.

Pharmacokinetics of Benzodiazepines

Absorption: Oral benzodiazepines are generally well-absorbed from the gastrointestinal tract, with the exception of clorazepate, which requires decarboxylation in gastric acid before absorption. Intramuscular (IM) absorption varies: diazepam and chlordiazepoxide absorption is slower compared to lorazepam and midazolam, which are absorbed more rapidly via the IM route. Intravenous (IV) administration results in rapid distribution to the brain and CNS, with highly lipophilic benzodiazepines like midazolam readily crossing the blood-brain barrier for quick onset of action.

Distribution: Benzodiazepines and their active metabolites exhibit high plasma protein binding. For example, plasma protein binding is approximately 70% for alprazolam, 85% for clonazepam, and 99% for diazepam. Benzodiazepine concentrations in cerebrospinal fluid are roughly equivalent to unbound drug concentrations in plasma. Diazepam demonstrates particularly rapid redistribution within the body.

Metabolism: Benzodiazepine metabolism typically involves three phases. Phase one involves N-desalkylation, producing biologically active metabolites, except for triazolam, alprazolam, and midazolam. Phase two involves hydroxylation, often yielding active derivatives. Phase three is conjugation with glucuronic acid. Hepatic CYP3A4 and CYP2C19 enzymes extensively metabolize most benzodiazepines. Lorazepam is an exception, undergoing direct glucuronidation without cytochrome P450 involvement, making it a suitable option for patients with hepatic dysfunction. Remimazolam is metabolized to CNS7054, a metabolite with minimal hypnotic activity.

Elimination: The kidneys are the primary route of excretion for benzodiazepines and their metabolites. Diazepam produces active metabolites like oxazepam, temazepam, and desmethyldiazepam, which contribute to its prolonged duration of action. The elimination half-life of benzodiazepines can be prolonged in elderly patients and those with renal dysfunction, impacting dosing considerations.

Administration Guidelines for Benzodiazepines

Available Dosage Forms and Strengths:

Benzodiazepines are commonly administered orally and intravenously. Alternative routes include rectal, intranasal, and intramuscular administration, particularly when oral or IV access is not feasible. Intranasal or IM routes can be valuable in actively seizing patients, while rectal administration in children is often used for seizure cessation before IV access is established.

Effective benzodiazepine administration involves incremental dosing until the desired clinical effects are achieved, such as sedation, seizure cessation, or anxiolysis. IV administration may take 3 to 5 minutes to reach sufficient CNS drug concentrations for the intended effect. Therefore, adequate time intervals between doses are crucial to prevent over-sedation.

Having resuscitation and airway management equipment readily available is paramount during benzodiazepine administration. This equipment may include nasopharyngeal and oropharyngeal airways, bag-valve masks, laryngeal mask airways, or endotracheal intubation, depending on the training and capabilities of the healthcare provider. Diazepam milligram equivalency can be used to estimate conversion factors between different benzodiazepines.

Adult Dosage Recommendations

• Alprazolam: For generalized anxiety disorder, initiate treatment at 0.25 to 0.5 mg three times daily, with possible increases every 3 to 4 days up to a maximum daily dose of 4 mg. Panic disorders may require 1 to 4 mg/day. Due to dependence potential, use the lowest effective dose.

• Chlordiazepoxide: For alcohol withdrawal syndrome, the initial dose is 50 to 100 mg, potentially followed by up to 300 mg/day as needed, guided by the CIWA-Ar protocol.

• Clonazepam: For panic disorder, the initial adult dose is 0.5 mg daily, with a typical maintenance dose of 1 mg daily. Seizure disorders may require 0.5 mg three times daily, with a maximum recommended daily dose of 20 mg.

• Clobazam: For Lennox-Gastaut syndrome (adjunct therapy), the initial dose for patients over 30 kg is 10 mg, increasing to 20 mg after one week, and a typical maintenance dose of 40 mg after two weeks. Lower doses are used for patients under 30 kg.

• Clorazepate: For focal (partial) onset seizures in patients over 12 years, the initial dose is 7.5 mg three times daily, with a maximum recommended dose of 90 mg/day.

• Diazepam: For severe alcohol withdrawal (CIWA-Ar ≥19), ASAM 2020 guidelines suggest front-loading regimens, such as 10 mg orally every hour for CIWA-Ar scores ≥10, or fixed schedules like 20 mg orally every 2 hours for three doses. Rectal diazepam for febrile seizures is dosed at 0.5 mg/kg.

• Estazolam: For sleep onset and sleep maintenance insomnia, the recommended estazolam dose is 1 to 2 mg at bedtime, according to AASM guidelines.

• Flurazepam: For insomnia treatment, the recommended flurazepam dose is 15 mg for women and 30 mg for men.

• Lorazepam: For convulsive status epilepticus, AES guidelines recommend IV lorazepam at 0.1 mg/kg as an initial dose, up to a maximum of 4 mg, which can be repeated every 3 to 5 minutes.

• Midazolam: For convulsive status epilepticus when IV access is unavailable, 10 mg IM midazolam is recommended as a single dose. Intranasal midazolam (0.2 mg/kg, max 10 mg) can be used pre-hospitally. Procedural sedation dosages vary based on the specific procedure and patient factors.

• Oxazepam: For alcohol withdrawal syndrome, symptom-triggered dosing is recommended. For CIWA-Ar scores of 8-15, 15 mg oxazepam is administered, and 30 mg for scores >15.

• Quazepam: For sleep onset and sleep maintenance insomnia, 7.5 mg quazepam daily at bedtime is recommended, with a potential increase to 15 mg, considering its long half-life and risk of accumulation.

• Temazepam: For sleep onset and sleep maintenance insomnia, AASM guidelines recommend 7.5 to 15 mg temazepam daily at bedtime. Cognitive behavioral therapy is the recommended first-line treatment for chronic insomnia according to ACP guidelines.

• Triazolam: For sleep-onset insomnia, the recommended dose is 0.125 to 0.25 mg daily at bedtime, limited to 4 to 8 weeks of use.

• Remimazolam: Remimazolam, approved in 2020, is indicated for short-duration sedation.

Specific Patient Population Considerations

• Hepatic Impairment: Lorazepam and oxazepam metabolism is minimally affected by liver disease. Lorazepam is often considered the safest benzodiazepine for alcohol withdrawal and hepatic impairment. Remimazolam should be used cautiously in severe hepatic impairment.

• Renal Impairment: Reduced clearance and plasma protein binding in renal impairment can lead to increased unbound benzodiazepine concentrations. Lorazepam may be relatively safe in ESRD patients, but diazepam carries an accumulation risk. Lower starting doses and careful titration to clinical response are essential.

• Pregnancy Considerations: Most benzodiazepines are categorized as former FDA pregnancy category D, indicating potential fetal risk. Diazepam and chlordiazepoxide have been linked to congenital malformations like cleft palate. Flurazepam and temazepam are considered pregnancy category X due to risks of neonatal lethargy and skeletal development issues. Benzodiazepines should generally be avoided, especially in the first trimester. NICE guidelines advise against benzodiazepines in pregnancy, although they may be used in severe anxiety, agitation, or seizures. Neonatal hypotonia and withdrawal are potential risks. Tapering benzodiazepines is recommended for women planning pregnancy.

• Breastfeeding Considerations: Caution is advised in neonates and preterm infants due to potential hypotension, especially with concurrent opioid use like fentanyl. Midazolam, lorazepam, and oxazepam may be used cautiously based on safety scoring systems. Benzodiazepine use during lactation should be avoided unless clearly necessary.

• Older Patients: The American Geriatric Society Beers Criteria identifies benzodiazepines as potentially inappropriate for older adults due to increased sensitivity and reduced clearance, raising risks of cognitive impairment, falls, and fractures. However, benzodiazepines may be warranted for seizure disorders, alcohol withdrawal, periprocedural sedation, and severe generalized anxiety disorder in older adults when benefits outweigh risks.

• Pediatric Patients: For seizures lasting at least 5 minutes in children, IV lorazepam and diazepam are effective. Rectal diazepam, IM midazolam, intranasal midazolam, and buccal midazolam are also likely effective seizure cessation options in pediatric patients.

Adverse Effects of Benzodiazepines

Benzodiazepine administration can result in various adverse effects, including respiratory depression, respiratory arrest, drowsiness, confusion, headache, syncope, nausea, vomiting, diarrhea, and tremors.

In neonates, less than 1% of benzodiazepine-treated patients may experience laryngospasm and bronchospasm. Cardiovascular effects can include ventricular arrhythmias (bigeminy, premature ventricular contractions), vasovagal syncope, bradycardia, or tachycardia. Gastrointestinal reactions may involve retching, nausea, vomiting, and excessive salivation. CNS and neuromuscular adverse effects can manifest as euphoria, hallucinations, ataxia, dizziness, seizure-like activity, and paresthesia.

Visual disturbances such as diplopia (double vision), cyclic eyelid movement, balance issues, and difficulty focusing can occur. Long-term benzodiazepine use is associated with potential cognitive impairment. Rare cases of cholestatic liver injury have been reported with benzodiazepines like alprazolam, clonazepam, diazepam, and flurazepam. Remimazolam use may lead to both hypertension and hypotension, necessitating blood pressure monitoring during procedures.

Drug-Drug Interactions

• Lorazepam and oxazepam are metabolized by uridine diphosphate glucuronosyltransferases (UGTs). UGT inducers like carbamazepine, phenobarbital, phenytoin, and rifampin can accelerate their metabolism and reduce efficacy, potentially diminishing the “benzo effect”.

Contraindications and Precautions for Benzodiazepine Use

Warnings and Precautions

Contraindications for benzodiazepines include known angle-closure glaucoma due to muscle relaxant effects that can affect the iris sphincter pupillae muscle. Hypersensitivity reactions are also a contraindication; anaphylaxis and angioedema have been reported. Remimazolam is contraindicated in patients with a history of hypersensitivity to dextran 40.

Box Warning

The concurrent use of benzodiazepines and opioids carries a significant risk of sedation, severe respiratory depression, coma, and death. This combination should be avoided whenever possible.

Monitoring During Benzodiazepine Therapy

Benzodiazepines are CNS depressants with respiratory depressant effects. Therefore, continuous monitoring of vital signs, especially blood pressure and respiratory rate, is crucial after benzodiazepine administration. Waveform capnography should be considered for enhanced respiratory monitoring. Despite a relatively high therapeutic index, vigilant monitoring for respiratory depression is essential, as respiratory arrest can occur with rapid IV injection.

For alcohol withdrawal management, the CIWA-Ar protocol should be used to monitor symptoms and adjust benzodiazepine dosage accordingly. Patients receiving parenteral lorazepam or diazepam for alcohol withdrawal should be monitored for hyponatremia and metabolic acidosis due to propylene glycol in IV formulations. In mechanically ventilated patients, the Richmond Agitation-Sedation Scale (RASS) should be monitored to prevent oversedation, aligning with Society of Critical Care Medicine (SCCM) guidelines for individualized patient-centered sedation approaches.

Prescription drug monitoring programs can assist healthcare professionals in identifying potential benzodiazepine misuse. Benzodiazepines are classified as DEA Schedule IV drugs; flunitrazepam is an exception within this class, carrying Schedule I penalties despite its Schedule IV classification.

Benzodiazepine Toxicity and Overdose Management

Signs and Symptoms of Overdose

Benzodiazepine overdose can manifest as extreme sedation, cognitive impairment, ataxia, and slurred speech. Respiratory depression is a critical and potentially life-threatening concern requiring immediate medical intervention. Cardiovascular effects, including hypotension and bradycardia, can also occur.

Management of Overdose

Benzodiazepine overdose management prioritizes airway, breathing, and circulation support, following American Heart Association (AHA) guidelines. Flumazenil, a GABA-A receptor antagonist, is a benzodiazepine reversal agent. It competitively inhibits benzodiazepines at the alpha-gamma subunit of the GABA-A receptor. However, flumazenil administration should be cautious, as it may precipitate withdrawal seizures in patients with benzodiazepine dependence. “Re-sedation” can occur as flumazenil effects wear off after significant benzodiazepine ingestion.

Naloxone may be considered if opioid co-ingestion is suspected in patients with respiratory distress or arrest. Lower naloxone doses (e.g., 0.05 mg) may be appropriate in suspected benzodiazepine-opioid co-ingestion to avoid opioid withdrawal-induced vomiting, which poses aspiration risks in sedated patients. Activated charcoal administration is generally contraindicated in benzodiazepine overdose due to the risk of aspiration in patients with altered mental status.

Recommendations for Overdose Management

The AHA 2023 guidelines provide recommendations for cardiac arrest or toxicity due to benzodiazepine poisoning. Isolated benzodiazepine poisoning rarely causes life-threatening hemodynamic instability or respiratory depression. Flumazenil can reverse benzodiazepine-mediated sympathetic system suppression, potentially leading to adverse cardiac events like supraventricular tachycardia, ventricular dysrhythmias, and asystole, especially with co-ingestion of arrhythmogenic drugs or hypoxia. Flumazenil may not fully reverse respiratory depression in mixed overdoses, and naloxone is often preferred when opioid co-ingestion is possible. The decision to use flumazenil should carefully consider the potential for mixed overdoses.

Enhancing Healthcare Team Outcomes in Benzodiazepine Therapy

Benzodiazepines are widely prescribed in both outpatient and inpatient settings. While effective for sedation and anxiolysis, they also carry risks. All healthcare professionals involved in prescribing and managing benzodiazepines must be fully aware of their adverse effects, misuse potential, abuse liability, and the risk of physical dependence. As DEA Schedule IV drugs, benzodiazepine prescriptions require careful management. Pharmacists play a vital role in medication reconciliation and identifying potential drug-drug interactions. Anesthesiologists and certified registered nurse anesthetists are crucial in procedural sedation involving benzodiazepines.

Nurses are essential for monitoring patients, particularly in mechanically ventilated settings. Neurologists should be consulted for specialized benzodiazepine use, such as clobazam for Lennox-Gastaut syndrome. Intensivists manage benzodiazepine sedation in critical care. Emergency medicine physicians and nurses are vital in stabilizing overdose patients. Psychiatrists are crucial in managing benzodiazepine use disorder and dependence once patients are stabilized. Overprescribing benzodiazepines is discouraged due to their abuse potential. Regulatory bodies like the DEA are increasingly scrutinizing healthcare professionals prescribing benzodiazepines without valid reasons and proper documentation.

Optimal benzodiazepine therapy necessitates a collaborative interprofessional healthcare team, including clinicians, specialists, pharmacists, and specialty-trained nurses. Team-based models involving clinical pharmacists and primary care physicians in anxiety and insomnia management can optimize therapy and minimize benzodiazepine-associated risks, ultimately improving patient outcomes and safety related to the “benzo effect”.

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References

1.Maust DT, Solway E, Clark SJ, Kirch M, Singer DC, Malani P. Prescription and Nonprescription Sleep Product Use Among Older Adults in the United States. Am J Geriatr Psychiatry. 2019 Jan;27(1):32-41. [PubMed: 30409547]

2.Blanco C, Han B, Jones CM, Johnson K, Compton WM. Prevalence and Correlates of Benzodiazepine Use, Misuse, and Use Disorders Among Adults in the United States. J Clin Psychiatry. 2018 Oct 16;79(6) [PMC free article: PMC10309967] [PubMed: 30403446]

3.Garakani A, Murrough JW, Freire RC, Thom RP, Larkin K, Buono FD, Iosifescu DV. Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options. Front Psychiatry. 2020;11:595584. [PMC free article: PMC7786299] [PubMed: 33424664]

4.March KL, Twilla JD, Reaves AB, Self TH, Slayton MM, Bergeron JB, Sakaan SA. Lorazepam versus chlordiazepoxide for the treatment of alcohol withdrawal syndrome and prevention of delirium tremens in general medicine ward patients. Alcohol. 2019 Dec;81:56-60. [PubMed: 31176787]

5.Isojarvi J, Gidal BE, Chung S, Wechsler RT. Optimizing clobazam treatment in patients with Lennox-Gastaut syndrome. Epilepsy Behav. 2018 Jan;78:149-154. [PubMed: 29202277]

6.Brigo F, Igwe SC, Bragazzi NL, Lattanzi S. Clonazepam monotherapy for treating people with newly diagnosed epilepsy. Cochrane Database Syst Rev. 2019 Nov 19;2019(11) [PMC free article: PMC6863099] [PubMed: 31742671]

7.Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. [PubMed: 18384456]

8.Chiang LM, Wang HS, Shen HH, Deng ST, Tseng CH, Chen YI, Chou ML, Hung PC, Lin KL. Rectal diazepam solution is as good as rectal administration of intravenous diazepam in the first-aid cessation of seizures in children with intractable epilepsy. Pediatr Neonatol. 2011 Feb;52(1):30-3. [PubMed: 21385654]

9.Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. 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 Feb 15;13(2):307-349. [PMC free article: PMC5263087] [PubMed: 27998379]

10.Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb;16(1):48-61. [PMC free article: PMC4749120] [PubMed: 26900382]

11.Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen JF, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e873. [PubMed: 30113379]

12.The ASAM Clinical Practice Guideline on Alcohol Withdrawal Management. J Addict Med. 2020 May/Jun;14(3S Suppl 1):1-72. [PubMed: 32511109]

13.Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD., Clinical Guidelines Committee of the American College of Physicians. Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Jul 19;165(2):125-33. [PubMed: 27136449]

14.Kilpatrick GJ. Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent. Front Pharmacol. 2021;12:690875. [PMC free article: PMC8329483] [PubMed: 34354587]

15.Poisbeau P, Gazzo G, Calvel L. Anxiolytics targeting GABAA receptors: Insights on etifoxine. World J Biol Psychiatry. 2018;19(sup1):S36-S45. [PubMed: 30204559]

16.Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. [PMC free article: PMC3504738] [PubMed: 23038269]

17.Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013 Summer;13(2):214-23. [PMC free article: PMC3684331] [PubMed: 23789008]

18.Sneyd JR, Rigby-Jones AE. Remimazolam for anaesthesia or sedation. Curr Opin Anaesthesiol. 2020 Aug;33(4):506-511. [PubMed: 32530890]

19.Wilcock A, Charlesworth S, Twycross R, Waddington A, Worthington O, Murtagh FEM, Beavis J, King S, Mihalyo M, Kotlinska-Lemieszek A. Prescribing Non-Opioid Drugs in End-Stage Kidney Disease. J Pain Symptom Manage. 2017 Nov;54(5):776-787. [PubMed: 28843456]

20.Borrelli EP, Bratberg J, Hallowell BD, Greaney ML, Kogut SJ. Application of a diazepam milligram equivalency algorithm to assess benzodiazepine dose intensity in Rhode Island in 2018. J Manag Care Spec Pharm. 2022 Jan;28(1):58-68. [PMC free article: PMC10373022] [PubMed: 34949119]

21.Melkonian A, Patel R, Magh A, Ferm S, Hwang C. Assessment of a Hospital-Wide CIWA-Ar Protocol for Management of Alcohol Withdrawal Syndrome. Mayo Clin Proc Innov Qual Outcomes. 2019 Sep;3(3):344-349. [PMC free article: PMC6713876] [PubMed: 31485573]

22.Ghazavi M, Nasiri J, Yaghini O, Soltani R. Oral Diazepam in Febrile Seizures Following Acellular Pertussis Vaccination. Adv Biomed Res. 2019;8:29. [PMC free article: PMC6507365] [PubMed: 31114769]

23.Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000 May 18;342(20):1471-7. [PubMed: 10816184]

24.Hughes CG, Mailloux PT, Devlin JW, Swan JT, Sanders RD, Anzueto A, Jackson JC, Hoskins AS, Pun BT, Orun OM, Raman R, Stollings JL, Kiehl AL, Duprey MS, Bui LN, O’Neal HR, Snyder A, Gropper MA, Guntupalli KK, Stashenko GJ, Patel MB, Brummel NE, Girard TD, Dittus RS, Bernard GR, Ely EW, Pandharipande PP., MENDS2 Study Investigators. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N Engl J Med. 2021 Apr 15;384(15):1424-1436. [PMC free article: PMC8162695] [PubMed: 33528922]

25.Gershkovich P, Wasan KM, Ribeyre C, Ibrahim F, McNeill JH. Effect of variations in treatment regimen and liver cirrhosis on exposure to benzodiazepines during treatment of alcohol withdrawal syndrome. Drugs Context. 2015;4:212287. [PMC free article: PMC4544271] [PubMed: 26322116]

26.Wyne A, Rai R, Cuerden M, Clark WF, Suri RS. Opioid and benzodiazepine use in end-stage renal disease: a systematic review. Clin J Am Soc Nephrol. 2011 Feb;6(2):326-33. [PMC free article: PMC3052223] [PubMed: 21071517]

27.Creeley CE, Denton LK. Use of Prescribed Psychotropics during Pregnancy: A Systematic Review of Pregnancy, Neonatal, and Childhood Outcomes. Brain Sci. 2019 Sep 14;9(9) [PMC free article: PMC6770670] [PubMed: 31540060]

28.Antenatal and postnatal mental health: clinical management and service guidance. National Institute for Health and Care Excellence (NICE); London: Apr, 2018. [PubMed: 31990493]

29.Shyken JM, Babbar S, Babbar S, Forinash A. Benzodiazepines in Pregnancy. Clin Obstet Gynecol. 2019 Mar;62(1):156-167. [PubMed: 30628916]

30.Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Jan 15, 2024. Lorazepam. [PubMed: 30000290]

31.Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Oct 15, 2024. Midazolam. [PubMed: 30000294]

32.Uguz F. A New Safety Scoring System for the Use of Psychotropic Drugs During Lactation. 2021 Jan-Feb 01Am J Ther. 28(1):e118-e126. [PubMed: 30601177]

33.By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023 Jul;71(7):2052-2081. [PubMed: 37139824]

34.Crowe SF, Stranks EK. The Residual Medium and Long-term Cognitive Effects of Benzodiazepine Use: An Updated Meta-analysis. Arch Clin Neuropsychol. 2018 Nov 01;33(7):901-911. [PubMed: 29244060]

35.LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jan 24, 2017. Benzodiazepines. [PMC free article: PMC547852] [PubMed: 31643621]

36.Lee A, Shirley M. Remimazolam: A Review in Procedural Sedation. Drugs. 2021 Jul;81(10):1193-1201. [PubMed: 34196946]

37.Weaver MF. Prescription Sedative Misuse and Abuse. Yale J Biol Med. 2015 Sep;88(3):247-56. [PMC free article: PMC4553644] [PubMed: 26339207]

38.Boulenc X, Nicolas O, Hermabessière S, Zobouyan I, Martin V, Donazzolo Y, Ollier C. CYP3A4-based drug-drug interaction: CYP3A4 substrates’ pharmacokinetic properties and ketoconazole dose regimen effect. Eur J Drug Metab Pharmacokinet. 2016 Feb;41(1):45-54. [PubMed: 25374256]

39.Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000 Jan;38(1):41-57. [PubMed: 10668858]

40.Park MY, Kim WJ, Lee E, Kim C, Son SJ, Yoon JS, Kim W, Namkoong K. Association between use of benzodiazepines and occurrence of acute angle-closure glaucoma in the elderly: A population-based study. J Psychosom Res. 2019 Jul;122:1-5. [PubMed: 31126405]

41.Haybarger E, Young AS, Giovannitti JA. Benzodiazepine Allergy With Anesthesia Administration: A Review of Current Literature. Anesth Prog. 2016 Fall;63(3):160-7. [PMC free article: PMC5011959] [PubMed: 27585420]

42.Shiratori T, Sato A, Fukuzawa M, Kondo N, Tanno S. Severe Dextran-Induced Anaphylactic Shock during Induction of Hypertension-Hypervolemia-Hemodilution Therapy following Subarachnoid Hemorrhage. Case Rep Crit Care. 2015;2015:967560. [PMC free article: PMC4480245] [PubMed: 26171255]

43.Aschenbrenner DS. Stronger Boxed Warning for Benzodiazepines. Am J Nurs. 2021 Mar 01;121(3):22-23. [PubMed: 33625005]

44.Hatlestad D. Capnography in sedation and pain management. Emerg Med Serv. 2005 Mar;34(3):65-9. [PubMed: 15839539]

45.Medlej K. Calculated decisions: Richmond Agitation-Sedation Scale (RASS). Emerg Med Pract. 2021 Mar 15;23(Suppl 3):CD3-CD4. [PubMed: 33729737]

46.Liang D, Guo H, Shi Y. Mandatory use of prescription drug monitoring program and benzodiazepine prescribing among U.S. Medicaid enrollees. Subst Abus. 2021;42(3):294-301. [PMC free article: PMC7202951] [PubMed: 31697195]

47.Panchal AR, Bartos JA, Cabañas JG, Donnino MW, Drennan IR, Hirsch KG, Kudenchuk PJ, Kurz MC, Lavonas EJ, Morley PT, O’Neil BJ, Peberdy MA, Rittenberger JC, Rodriguez AJ, Sawyer KN, Berg KM., Adult Basic and Advanced Life Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16_suppl_2):S366-S468. [PubMed: 33081529]

48.Gallo AT, Hulse G. Pharmacological uses of flumazenil in benzodiazepine use disorders: a systematic review of limited data. J Psychopharmacol. 2021 Mar;35(3):211-220. [PubMed: 33426982]

49.Sivilotti ML. Flumazenil, naloxone and the ‘coma cocktail’. Br J Clin Pharmacol. 2016 Mar;81(3):428-36. [PMC free article: PMC4767210] [PubMed: 26469689]

50.Zellner T, Prasa D, Färber E, Hoffmann-Walbeck P, Genser D, Eyer F. The Use of Activated Charcoal to Treat Intoxications. Dtsch Arztebl Int. 2019 May 03;116(18):311-317. [PMC free article: PMC6620762] [PubMed: 31219028]

51.Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, Cao D, Hoffman RS, Hoyte CO, Mazer-Amirshahi ME, Stolbach A, St-Onge M, Thompson TM, Wang GS, Hoover AV, Drennan IR., American Heart Association. 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023 Oct 17;148(16):e149-e184. [PubMed: 37721023]

52.Jørgensen MB, Osler M. Should benzodiazepines be avoided? Acta Psychiatr Scand. 2018 Aug;138(2):89-90. [PubMed: 30398297]

53.Revet A, Yrondi A, Montastruc F. [Good practices in prescribing benzodiazepines]. Presse Med. 2018 Oct;47(10):872-877. [PubMed: 30385184]

54.Furbish SML, Kroehl ME, Loeb DF, Lam HM, Lewis CL, Nelson J, Chow Z, Trinkley KE. A Pharmacist-Physician Collaboration to Optimize Benzodiazepine Use for Anxiety and Sleep Symptom Control in Primary Care. J Pharm Pract. 2017 Aug;30(4):425-433. [PMC free article: PMC5511764] [PubMed: 27480874]

Disclosure: Connor Bounds declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.