Amp. Ampoule

BDZ Benzodiazepine

EtOH Ethanol

h Hour

IM Intramuscular

IV Intravenous

Min Minute

NIMV Non-invasive mechanical ventilation

PO Oral

R Rectal

SE Status epilepticus

SL Sublingual

Tab. Tablet

TTPE Time to peak effect

Injectable diazepam Black Box Warning (14)(applicable to all benzodiazepines):
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; AND DEPENDENCE AND WITHDRAWAL REACTIONS

• Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

• Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.

• Limit dosages and durations to the minimum required.

• Follow patients for signs and symptoms of respiratory depression and sedation.

• The use of benzodiazepines, including diazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing diazepam and throughout treatment, assess each patient's risk for abuse, misuse, and addiction.

• The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although diazepam is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of diazepam may precipitate acute withdrawal reactions, which can be life-threatening. For patients using diazepam more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam.

(Updated April 4, 2023)

Comments

• Overall, more high-quality studies (RCTs, systematic reviews and meta-analyses) are needed to determine which benzodiazepine is most effective for various indications used in emergency medicine, including the optimal route of administration for specific indications.

• Usage of a specific benzodiazepine for a given clinical scenario should be decided with caution, as it may vary depending on individual characteristics. The provider's experience with a particular benzodiazepine should also be taken into consideration

• Differences on reported timing of onset, peak effect and duration of action of BDZ:
  Variations may be affected depending on the dose of the benzodiazepine, individual factors such as metabolism, age, sex, weight, comorbidities, and drug interactions. 

• Differences on reported elimination half-life of benzodiazepines:
  Differences may be due to whether the measurement includes the active metabolites of the drug that can accumulate in the body contributing to an increased effect duration. 

  • Hepatic metabolism of diazepam produces several active metabolites, including nordiazepam, temazepam, and oxazepam, each with their own pharmacological effects and contribute to the overall duration of action of the drug.

  • Clonazepam is metabolized in the liver to form an active metabolite called 7-aminoclonazepam, which has a half-life of approximately 50 hours.

  • Midazolam is metabolized in the liver to form an active metabolite called alpha-hydroxymidazolam, which has a half-life of approximately 6-10 hours. 

  • Lorazepam is metabolized in the liver to form an inactive metabolite called lorazepam glucuronide, as well as a minor active metabolite called 3-hydroxylorazepam. The elimination half-life of lorazepam is determined primarily by the inactive metabolite, which has a half-life of approximately 12-16 hours. 

• For PO administration, diazepam has a faster TTPE than oral lorazepam and oxazepam, and has lower incidence of rebound phenomena (9).

Related drugs

• Benzodiazepines

  • Lorazepam

  • Midazolam

  • Diazepam

  • Clonazepam

• Other

  • Drugs for intramuscular use in agitation

  • Olanzapine

  • Droperidol

  • Ketamine

  • Levetiracetam

  • Phenytoin

  • Valproic acid

  • Propofol

  • Etomidate

• EMupdates: Intramuscular Benzodiazepines: Use Midazolam (2009)

• CORE EM: Parenteral Benzodiazepines (2016)

• EM Cases: Episode 87 – Alcohol Withdrawal and Delirium Tremens: Diagnosis and Management (2016)

• RCEM: Procedural sedation in Emergency Medicine (2020)

1. Greenblatt DJ, Harmatz JS, Friedman H, Locniskar A, Shader RI. A large-sample study of diazepam pharmacokinetics. Ther Drug Monit. 1989;11(6):652-657. doi:10.1097/00007691-198911000-00007
   Pubmed

2. Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy. 1996;16(1):49-57.
   Pubmed

3. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Acad Emerg Med. 2004;11(7):744-749. doi:10.1197/j.aem.2003.06.015
   Academic Emrgency Medicine (Open Access)

4. RAMPART: Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600. doi:10.1056/NEJMoa1107494
   NEJM (Open Access)

5. Griffin CE 3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13(2):214-223.
   Pubmed

6. Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2014;2014(9):CD003723. Published 2014 Sep 10. doi:10.1002/14651858.CD003723.pub3
   Pubmed

7. Vuyk J, Sitsen E, Reekers M. Intravenous Anesthesia. In: Miller, R.D. (2015) Miller’s Anesthesia. 8th Edition, Saunders; 2015.
   Elsevier

8. Mihic S, Mayfield J, Harris R. Hypnotics and Sedatives. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill; 2017.
   McGraw-Hill

9. Weintraub SJ. Diazepam in the Treatment of Moderate to Severe Alcohol Withdrawal. CNS Drugs. 2017 Feb;31(2):87-95. doi: 10.1007/s40263-016-0403-y. PMID: 28101764.
   Pubmed

10. Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074-D1082. doi:10.1093/nar/gkx1037
    Pubmed

11. ACEP Task Force Report on Hyperactive Delirium with Severe Agitation in Emergency Settings. Approved by the ACEP Board of Directors, June 23, 2021.
    ACEP (Open Access)

12. Trinka E, Leitinger M. Management of Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus. Continuum (Minneap Minn). 2022;28(2):559-602. doi:10.1212/CON.0000000000001103
    Pubmed

13. NIH-NLM (National Institutes of Health - National Library of Medicine). Dailymed. Label: Clonazepam tablet, orally disintegrating. Updated in November 2022, accessed February 8, 2023.
    DailyMed

14. NIH-NLM (National Institutes of Health - National Library of Medicine). Dailymed. Label: Diazepam injection, solution. Updated in November 2022, accessed February 8, 2023.
    DailyMed

15. NIH-NLM (National Institutes of Health - National Library of Medicine). Dailymed. Label: Ativan - lorazepam injection. Updated in November 2022, accessed February 8, 2023.
    DailyMed

16. NIH-NLM (National Institutes of Health - National Library of Medicine). Dailymed. Label: Seizalam - midazolam hydrochloride injection, solution. Updated in January 2023, accessed February 8, 2023.
    DailyMed