Benzodiazepine Comparison Table – IV and Oral

Benzodiazepines are prescribed to over 5% of the United States population and that number continues to grow. This class of medications is responsible for facilitating the binding of the inhibitory neurotransmitter GABA-A at various GABA receptors throughout the central nervous system. GABA is the most common neurotransmitter in the central nervous system, found in high concentrations in the cortex and limbic systems. Benzodiazepines have been used for a variety of indications including anxiety, insomnia, muscle relaxation, seizures, and alcohol withdrawal syndrome. As displayed in the benzodiazepine comparison table below, diazepam and midazolam are also used as sedatives prior to or during medical operations. 

IV and Oral Benzodiazepine Comparison Table





Drug (Brand)



Approved Formulations 



Primary Metabolic Pathway




Onset




Half-life (hrs)
Alprazolam (Xanax) Tablet: 0.25mg, 0.5mg, 1mg, 2mg
Orally Disintegrating Tablet: 0.25mg, 0.5mg, 1mg, 2mg
CYP3A4Intermediate (1-1.5 hours)16-20(intermediate)
Midazolam (Versed)Injection: 1mg/mL, 5mg/1 mLCYP3A4Fast (Injectable only)(1-15 minutes)3-8 (short)
Clonazepam (Klonopin)Tablet: 0.5mg, 1mg, 2mg
Orally Disintegrating Tablet: 0.125mg, 0.25mg, 0.5mg, 1mg, 2mg
CYP3A4 NAT2Intermediate(1-4 hours)30-50 (long)
Temazepam (Restoril)Capsule: 7.5mg, 15mg, 22.5mg, 30mgCYP3A4CYP2C19Intermediate(45 minutes-1.5 hours)3.5-18(Short)
Diazepam (Valium) Tablet: 2mg, 5mg, 10mg
Injection: 5mg/1mL
CYP3A4 CYP2C19Fast (oral)(30 minutes-1.5 hours)Injectable – rapid20-100(long)
Lorazepam (Ativan)Tablet: 0.5mg, 1mg, 2mg
Injection: 2mg/1mL, 4mg/1mL
UGT2B15Intermediate (oral)(2-3 hours)Injectable – rapid11-20 (intermediate)
Oxazepam (Serax)
Capsule: 10mg, 15mg, 30mgUGT2B15UGT1A9UGT2B7Intermediate(2-3 hours)5-15 (short)
Triazolam (Halcion)Tablet: 0.125mg, 0.25mgCYP3A4Fast(15-30 minutes)1.5-5.5(short)
Chlordiazepoxide (Librium)Capsule: 5mg, 10mg, 25mgCYP3A4Variable(30 minutes- 6 hours)24-48 (long)
The benzodiazepine class of medications are considered to have a tranquilizing effect in patients, so it is important patients understand how it affects them before operating heavy machinery or driving a vehicle. Some common adverse effects that can be seen with these medications include sedation, drowsiness, confusion, dizziness, impaired balance and coordination, memory impairment, blurred vision, insomnia, and anxiety.

All benzodiazepines besides lorazepam, oxazepam, and temazepam are primarily metabolized by CYP3A4 leading to the potential for drug-drug interactions. The inhibition of CYP3A4 leads to an increase in benzodiazepine concentration in the body and increases the risk for adverse events or toxicity. Examples of CYP3A4 inhibitors include erythromycin, amiodarone, grapefruit juice, oral contraceptives, and fluvoxamine. If taken simultaneously with any of the listed medications patients may need a decreased dose of benzodiazepine to avoid the potential for adverse events. Oppositely, the induction of CYP3A4 by medications like carbamazepine, phenytoin, rifampin, and St. John’s wort can lead to decreased levels of benzodiazepines and need for increased doses to potentiate the desired effectiveness.

It is important to understand that benzodiazepines are schedule 4 controlled substances and have the potential for not only dependence but also severe withdrawal if used for extended periods of time. It is generally recommended that these medications are used on an as-needed basis and for a short period of time (2-4 weeks). If patients need to be on these medications longer than this duration, tapering needs to be considered to prevent the potential for severe withdrawal symptoms (rebound anxiety, insomnia, restlessness, twitches, sweating, GI complaints, and seizure). 

Clinical Pearls: Comparing The Benzodiazepines

The most commonly prescribed benzodiazepines are clonazepam, lorazepam, diazepam, and alprazolam. As noted in the benzodiazepine comparison table above, lorazepam is not metabolized by CYP3A4. This medication may be used preferentially when patients are on medications that either induce or inhibit CYP3A4 to provide patients with adequate symptom relief while negating the potential for variable concentrations. 

Geriatric patients are commonly prescribed benzodiazepines for increased anxiety and insomnia symptoms. It is important to recognize that this population is particularly vulnerable to the risks associated with benzodiazepine use (impaired coordination, sedation, confusion) leading to falls due to decreased organ metabolic function. 

The acronym LOT is used to identify specific benzodiazepines that are potentially safer in the geriatric population. These medications have shorter half-lives and lack of (or rapid disappearance of) active metabolites produced by their mode of metabolism. This means that older adults who are on these medications for short-term treatment may experience less drug accumulation and impaired cognition. Although these medications are “safer” to be used in the geriatric population, it is important to remember that benzodiazepines in general should be avoided if possible.

Another acronym along the same lines as “LOT” is the acronym “LO”. Lorazepam and oxazepam avoid the CYP3A4 pathway so if you have a patient who is taking drugs that impact CYP3A4, it might be advisable to utilize one of these agents. Lorazepam is the one you are most likely to see in practice. 

Another fun and final acronym that may help you identify medications commonly used for anxiety symptoms is using the saying, “un-do anxiety with un-CLAD.” The medicines I am specifically referring to here are clonazepam, lorazepam, alprazolam, and diazepam as they all have fast to intermediate onset with longer half-lives leading to adequate daytime anxiety reduction.

Article and Table written and created by Jeff Mueller, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP

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References:

1. Maust DT, Blow FC, Wiechers IR, et al.: National trends in antidepressant, benzodiazepine, and other sedative-hypnotic treatment of older adults in psychiatric and primary care. J Clin Psychiatry 2017; 78:e363–e371

2. Fox C, Liu H, Kaye AD. Manchikanti L, Trescot AM, Christo PJ, et al, eds. Clinical Aspects of Pain Medicine and Interventional Pain Management: A Comprehensive Review. Paducah, KY: ASIP Publishing;; 2011. Antianxiety agents; pp. 543–552. In.

3. Rail TW. Hypnotics and sedatives: ethanol. In: Gilman AG, Rail TW, Nies AS, Taylor P, editors. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 8th ed. New York: Pergamon Press, 1990: 353-354.

4. Package inserts and Micromedex for each individual medication for preparation of the table. 

5. Nemeroff CB. Anxiolytics: past, present, and future agents. J Clin Psychiatry. 2003;64 Suppl 3:3-6

6. Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65 Suppl 5:7-12. 

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Written By Eric Christianson

October 16, 2022

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