The ABCs of BZDs: What You Need To Know About Benzodiazepines

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Lorazepam, diazepam, midazolam: What’s the difference? 

Benzodiazepines (BZDs) are used on a daily basis in the ED. We routinely reach for lorazepam, diazepam, midazolam and other BZDs to treat seizures, alcohol withdrawal and acute agitation, and hiommonly administer them for anxiolysis and procedural sedation. But how do the various BZDs differ? Are particular BZDs preferred in certain conditions? Let’s review the common BZDs and their indications.

The ABCs of BZDs
BZDs have a broad spectrum of clinical activity. Properties of BZDs include anxiety reduction, sedation, sleep induction, anticonvulsant effects, and muscle relaxation [1]. BZDs have high efficacy rates, rapid onset of action, and relatively low toxicity, making them among the most commonly prescribed classes of drugs. In addition, BZDs can be administered via a number of routes—oral, intravenous, intramuscular, buccal, rectal, and intranasal—making them very useful in hospital, pre-hospital, and outpatient settings.

How They Work
BZDs are sedative hypnotic agents that exert their effect by potentiating actions of the neurotransmitter GABA. BZDs bind to the GABA receptors at a site distinct from where GABA binds, and increases the frequency of gated channel opening, thereby enhancing conduction and increasing GABA-mediated inhibition [1].

Wait—They’re Not All the Same?
The different BZDs have distinct pharmacokinetic properties—varied absorption, onset, and duration of action—making them useful in different conditions. BZDs are classified as low, medium, or high potency. Most of the BZDs we use in the ED are either medium (diazepam) or high potency (clonazepam, lorazepam). BZDs are also classified based on their onset of action and duration, which helps guide which one should be used for a given circumstance. For example, in procedural sedation, shorter-acting BZDs are preferred, like midazolam, whereas an agent with a longer duration of action like diazepam is selected when prolonged drug action is needed, such as in the management of alcohol withdrawal.

BZDs Are Tricky
As efficacious and useful as these drugs are, BZDs have significant adverse effects if used at doses that are too high. They can cause drowsiness, oversedation, respiratory depression, amnesia, and ataxia, and are associated with increased risk of falls and traffic accidents [1,2]. BZDs should be used with caution in the elderly, who have decreased protein-drug binding and decreased renal and hepatic clearance, making them much more sensitive to these drugs. As a rule of thumb for elderly patients, half of the typical adult dose should be used, and BZDs should not be prescribed for long-term use.

Recently in the News
BZDs are dangerous when combined with other CNS depressants like alcohol and opioids, and can cause fatal CNS and respiratory depression. For this reason, in 2016 the FDA issued a boxed warning about the dangers of co-administering opioid to patients taking BZDs [1].

Dependence and Withdrawal 
While ED use of BZDs is generally safe, long-term use is problematic and associated with dependence. Shockingly, BZD dependence develops in approximately half of patients who use BZDs for greater than one month [2]. Potent BZDs with shorter half-lives, such as alprazolam and lorazepam, are linked to higher risk of dependence. Abrupt cessation of chronic BZD use is also associated with a withdrawal syndrome, characterized by CNS hyperexcitability, and symptoms such as anxiety, restlessness, agitation, hallucinations, delirium, and seizures. For this reason, chronic BZD use should be discontinued gradually over a period of 4-6 weeks [2].

Use in Status Epilepticus
BZDs are first-line agents for termination of seizures in status epilepticus. If IV access is available, lorazepam 4 mg IV (0.1 mg/kg IV, in children, max 4 mg) should be administered, and repeated in 5 minutes as needed. Onset of action is within 2 minutes, and duration is 4-6 hours. Diazepam (0.15 mg/kg IV in adults, 0.2 mg/kg IV in children) is an alternative [3]. Efficacy of lorazepam and diazepam at terminating seizures is similar, though studies show a trend toward improved efficacy in lorazepam [1]. A unique benefit of diazepam is that it remains stable in pre-mixed liquid form, unlike lorazepam and midazolam. This makes it more convenient for pre-hospital settings. Diazepam is also available in a rectal gel, and many families use this at home to terminate seizures in children with epilepsy [3].

Midazolam is also effective in status epilepticus, but is second-line after lorazepam and diazepam due to its short half-life and risk of recurrent seizure. However, if IV access is unavailable, IM midazolam is the drug of choice [4]. The dose of midazolam in status epilepticus is 10 mg IM (in children, 5 mg for 13-40 kg and 10 mg for > 40 kg). Doses may be repeated after 10-15 minutes. Midazolam also has the advantage of administration via buccal and intranasal routes. One study showed that buccal midazolam was more effective in terminating seizures in children than rectal diazepam [3]. A buccal formulation of midazolam is not currently available in the United States, but some trials have used the intravenous formulation of midazolam for buccal use. The dose of midazolam for buccal administration is 0.5 mg/kg for adults and children. For intranasal use, the most concentrated intravenous solution should be used (5 mg/mL), to avoid having too much volume administered into the nose. The dose of intranasal midazolam is 0.2 mg/kg for adults and children, max dose 10 mg for children [4].

Use in Alcohol Withdrawal
BZDs are commonly used to treat the psychomotor agitation experienced by patients withdrawing from alcohol, and to prevent development of serious complications, such as delirium, hallucinations, and seizures. While all BZDs could theoretically work, long-acting BZDs with active metabolites such as diazepam and chlordiazepoxide are preferred due to more consistent drug levels and decreased chance of symptom recurrence [5]. On the other hand, for patients with advanced liver disease, which is true of many alcoholics, a BZD with a moderate duration of action may be preferred, like lorazepam, because it may help avoid oversedation in a patient with impaired hepatic clearance [5].

Use in Procedural Sedation and Anxiolysis
Midazolam is the BZD of choice for procedural sedation, due to its rapid onset and short duration of action. Onset is typically within 2-5 minutes, with duration lasting 30-60 minutes [6]. Lorazepam and diazepam are less commonly used because they have a longer duration of action, and produce less amnesia compared to midazolam [6]. The dose of midazolam for procedural sedation is 0.02 to 0.03 mg/kg IV, typical dose 0.5 to 2 mg at a time, titrated to effect. In children, the dose is 0.025 to 0.05 mg/kg IV. Lower doses should be used in the obese, the elderly, and those with renal or hepatic disease who are at greater risk of respiratory depression and prolonged sedation.

Midazolam is often given for anxiolysis prior to having children. The dose is 0.25 to 0.5 mg/kg by mouth, or 0.2 to 0.3 mg/kg intranasally, maximum dose 10 mg [7].

Should We Use Flumazenil in BZD Overdose?
Flumazenil is a competitive antagonist of the BZD receptor and reverses BZD-induced sedation. However, use of flumazenil is controversial, because it can precipitate withdrawal seizures in patients who take chronic BZDs, and then since the receptor is blocked, BZDs would be ineffective in terminating the seizures. A secondary issue is that flumazenil does not consistently reverse respiratory depression caused by BZDs [8]. The consensus seems to be that flumazenil should only be used when the risk of BZD overdose outweighs the risk of flumazenil use, such as to avoid endotracheal intubation in a BZD-naive patient who was inadvertently oversedated during procedural sedation.

Benzo Briefing

  1. BZDs are first-line agents for status epilepticus, and lorazepam and diazepam have similar efficacy.
  2. For seizing patients without IV access, consider midazolam via intramuscular, buccal, or in-tranasal routes.
  3. For alcohol withdrawal, select a long-acting BZD like diazepam or chlordiazepoxide, but choose a more moderate-acting BZD like lorazepam if there is significant liver disease.
  4. For procedural sedation, midazolam is the BZD of choice.
  5. Use caution with BZDs in the elderly. Start at half the usual dose, and avoid prescribing for chronic use.
  6. BZDs are great for use in the ED, but be very wary of prescribing for long-term use, due to the risk of dependence, abuse, and addiction.

REFERENCES

  1. Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: Pharmacology and pharmacokinetics. Acta Neurol Scand. 2008;118(2):69-86.
  2. Soyka M. Treatment of benzodiazepine dependence. N Engl J Med. 2017;376(12):1147-1157. doi: 10.1056/NEJMra1611832 [doi].
  3. Wilfong A. Management of convulsive status epilepticus in children. Uptodate Web site. www.uptodate.com. Updated 2016. Accessed June 15, 2017.
  4. Lexicomp: Midazolam: Drug information. www.uptodate.com.
  5. Hoffman R, Weinhouse G. Management of moderate and severe alcohol withdrawal. Uptodate Web site. www.uptodate.com. Updated 2017. Accessed June 15, 2017.
  6. Frank R. Procedural sedation in adults outside the operating room. Uptodate Web site. www.uptodate.com. Updated 2017. Accessed June 15, 2017.
  7. Hsu,D., Cravera,J. Procedural sedation in children outside of the operating room. Uptodate Web site. www.uptodate.com. Updated 2016. Accessed June 15, 2017.
  8. Lexicomp: Flumazenil: Drug information. www.uptodate.com. Accessed June 15, 2017.

ABOUT THE AUTHORS

Karen Serrano, MD is an assistant professor in the department of emergency medicine at the University of North Carolina.

Dr. Shenvi is an assistant professor in the department of emergency medicine at the University of North Carolina. She authors RX Pad each month in EPM.

2 Comments

  1. In the section “Use in Procedural Sedation and Anxiolysis” you state, “Midazolam is often given for anxiolysis prior to children.” There could be some missing words here so I thought I’d offer a few helpful suggestions:

    Midazolam is often given for anxiolysis prior to having children.
    Midazolam is often given for anxiolysis prior to raising children.
    Midazolam is often given for anxiolysis prior to children completing adolescence.
    Midazolam is often given for anxiolysis prior to children telling you what college will cost.
    Midazolam is often given for anxiolysis prior to children telling you they are coming back to live with you after completing college.

    I hope one of these is what you had in mind.

    Thanks for the helpful review.

  2. I notice someone has apparently followed my first suggestion and changed the text to read, “Midazolam is often given for anxiolysis prior to having children.” I don’t know who did this, but apparently the authors are not paying attention. It just goes to show that it pays to be careful about joking because someone is likely to take you seriously. In case it’s not obvious, yes there is something missing from the original sentence, but “having” and the rest of my suggestions are not it (I hope).

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