Johns Hopkins Psychiatry Guide
Benzodiazepines
DRUG CLASS
- Anxiolytics
INDICATIONS
FDA
- Generalized anxiety disorder (GAD)
- Social phobia
- Panic disorder
- Insomnia
- Status epilepticus/seizures
- Premedication for anesthetic procedures
NON-FDA APPROVED USES
- Agitation
- Alcohol withdrawal symptoms
- Muscle spasms
- Sedation
- Restless legs syndrome
- Sleepwalking disorder
MECHANISM
- Benzodiazepines act through the gamma-aminobutyric acid (GABA) A receptor, which regulates chloride entry into neurons, resulting in neuronal hyperpolarization[1].
FORMS
brand name | preparation | manufacturer | route | form | dosage | cost* |
Xanax | Alprazolam | Pfizer Multiple generic manufacturers | PO | Tablet ER tablet ODT Liquid | 0.25 mg to 1 mg three times a day Maximum 4 mg/day | Tablets: Brand: 0.25 mg (100): $241.39 0.5 mg (100): $300.72 1 mg (100): $410.72 2 mg (100): $682.27 Generic: 0.25 mg (100): $69.50 0.5 mg (60): $128.95 1 mg (60): $160.40 2 mg (60): $212.90 3 mg (60): $319.35
Brand: 0.5 mg (60): $299.93 1 mg (60): $373.20 2 mg (60): $495.34 3 mg (60): $742.93 Generic: 0.5 mg (60): $135.40 1 mg (60): $168.46 2 mg (60): $223.58 3 mg (60): $335.36
0.25 mg (100): $218.26 0.5 mg (100): $271.93 1 mg (100): $362.81 2 mg (100): $616.91 Liquid (1 mg/mL, 30-mL bottle): Generic only: $81.05 |
Librium | Chlordiazepoxide | Multiple generic manufacturers | PO | Capsule | 5 to 25 mg three times a day-four times a day Maximum 100 mg/day | 5 mg (100): $35.25 10 mg (100): $39.78 25 mg (100): $42.84 |
Klonopin | Clonazepam | Roche Multiple generic manufacturers | PO | Tablet ODT | 0.5 to 1 mg three times a day Maximum 20 mg/day | Tablets: Brand: 0.5 mg (100): $245.48 1 mg (100): $280.03 2 mg (100): $388.01 Generic: 0.5 mg (100): $74.95 1 mg (100): $85.55 2 mg (100): $118.45 ODT: Generic: 0.125 mg (60): $77.93 0.25 mg (60): $77.93 0.5 mg (60): $77.80 1 mg (60): $88.91 2 mg (60): $123.19 |
Valium | Diazepam | Roche Multiple generic manufacturers | PO | Tablet Liquid | 5 to 25 mg three times a day-four times a day Maximum 40 mg/day | Tablet: Brand: 2 mg (100): $327.06 5 mg (100): $508.68 10 mg (100): $856.28 Generic: 2 mg (100): $10.45 5 mg (100): $16.35 10 mg (100): $31.25 Liquid (5 mg/5 mL, 500-mL bottle): Generic only: $67.83 |
Ativan | Lorazepam | Multiple generic manufacturers | PO | Tablet Liquid | 0.5 to 1 mg three times a day-four times a day | Tablet: Brand: 0.5 mg (100): $898.14 1 mg (100): $1199.78 2 mg (100): $1912.10 Generic: 0.5 mg (100): $67.75 1 mg (100): $88.25 2 mg (100): $128.45 Liquid (2 mg/1 mL, 30-mL bottle): Generic only: $39.60 |
Serax | Oxazepam | Multiple generic manufacturers | PO | Capsule | 10 to 30 mg three times a day-four times a day | 10 mg (100): $115.19 15 mg (100): $145.45 30 mg (100): $210.39 |
ODT = orally disintegrating tablets
ER = extended release
*Prices represent cost per unit specified, and are representative of "Average Wholesale Price" (AWP)
ADULT DOSING
USUAL
- The dosage of a benzodiazepine will vary depending on the patient and his or her history of sedative use.
- Although similar in many ways, the choice of an agent is often based on its pharmacokinetic properties, especially onset of action, half-life, and metabolic pathway.
- Oral dose equivalences of benzodiazepines[2]:
Agent | Relative Potency (mg) |
Alprazolam (Xanax XR®; Xanax®) | 0.5 |
Chlordiazepoxide (Librium®) | 10 |
Clonazepam (Klonopin®) | 0.25-0.5 |
Diazepam (Diastat®, Valium®) | 5 |
Lorazepam (Ativan®) | 1 |
Oxazepam (Serax®) | 15-30 |
- Alprazolam (Xanax®): The initial dose is 0.25 mg two to three times a day; the dose can be increased by 0.5-1 mg daily every 3-4 days; the usual therapeutic dose is 2-3 mg total/day, with twice daily or three times a day dosing. The maximum dose is 4 mg/day.
- Chlordiazepoxide (Librium®): The initial oral dose is 5-10 mg daily to twice a day; the dose can be increased by 5 mg daily; the usual therapeutic dose is 30-40 mg total/day, with twice daily or three times a day dosing. An intramuscular dose (not available in the U.S.) of 50-100 mg can be given every 4 hours if needed for alcohol withdrawal.
- Clonazepam (Klonopin®): The initial dose is 0.25 mg daily to twice a day; the dose can be increased by 0.125-0.25 mg daily or two times a day every 2-3 days; the usual therapeutic dose is 1-4 mg total/day in divided doses.
- Diazepam (Valium®): The initial dose is 2 mg two to four times a day; the dose can be increased by 1-2 mg daily; the usual therapeutic dose is 15-30 mg total/day, with twice daily or three times a day dosing. An IM dose of 10 mg can be administered every 4 hours if needed for alcohol withdrawal.
- Lorazepam (Ativan®): The initial dose is 0.5 mg twice a day; the dose can be increased by 1 mg daily in divided doses (twice daily or three times a day); the usual therapeutic dose is 2-8 mg total/day, with twice daily or three times a day dosing.
- Oxazepam (Serax®): the initial dose is 10-15 mg daily; the dose can be increased by 10 mg daily in divided doses (three times a day); the usual therapeutic dose is 90 mg total/day, with three times a day dosing.
GERIATRIC
Elderly patients often require lower benzodiazepine doses due to slower metabolism of the drugs.
- Alprazolam: No dose adjustment is needed; increase as needed/tolerated
- Chlordiazepoxide: Decrease the usual dose by 50%
- Clonazepam: No dose adjustment is needed; increase as needed/tolerated
- Diazepam: Use 2 mg daily initially, and increase as needed/tolerated
- Lorazepam: Use an initial dose of 1 mg/day in divided doses, and increase as needed/tolerated
- Oxazepam: The maximum dose is 45-60 mg total/day, in divided doses
RENAL
- Alprazolam: No dose adjustment is needed; increase as needed/tolerated
- Chlordiazepoxide: Patients with renal impairment (CrCl less than 10 mL/min) should have their doses decreased by 50%
- Clonazepam: No dose adjustment is needed; increase as needed/tolerated
- Diazepam: No dose adjustment is needed; increase as needed/tolerated
- Lorazepam: No dose adjustment is needed for mild-to-moderate renal impairment; not recommended for patients with renal failure
- Oxazepam: No dose adjustment is needed; increase as needed/tolerated
HEPATIC
- Alprazolam: No dose adjustment is needed; increase as needed/tolerated
- Chlordiazepoxide: The maximum dose is 20 mg total/day
- Clonazepam: No dose adjustment is needed; increase as needed/tolerated
- Diazepam: Reduce the usual dose by 50%
- Lorazepam: No dose adjustment is needed for mild-to-moderate liver impairment; not recommended for patients with hepatic failure
- Oxazepam: No dose adjustment is needed; increase as needed/tolerated
PREGNANCY
- Benzodiazepines are category D drugs, primarily due to concerns with cleft lip/palate and urogenital and neurological malformations; however, recent literature does not show an increased risk of these[3].
- When possible, avoid use during the first trimester
- Minimize use; i.e., reserve for PRN use if possible
- Weigh the benefit vs. the risk of continued therapy; if necessary, consider an agent with a short half-life, and use sparingly and intermittently
- Consider initiating and/or maintaining patients on an antidepressant agent. With the exception of paroxetine (category D), all the antidepressants are in category C
- Avoid use near the time of delivery, as the baby may experience withdrawal symptoms
BREASTFEEDING
- Long-term effects from exposure are unknown, but all benzodiazepines can cross into the breast milk; thus, the baby may experience side effects, including respiratory depression, sedation, difficulty breastfeeding and hypotonia - also known as “floppy baby syndrome.”
- In general, benzodiazepines may have a longer half-life in babies (who have not developed the mechanisms for metabolism).
- If used, choose an agent with a shorter half-life.
PEDIATRIC DOSING
USUAL
- Alprazolam: Safety has not been established in children
- Chlordiazepoxide: Not recommended for children younger than 6 years of age. For children older than 6 years of age, use 5 mg two to four times a day. This can be increased to 10 mg two to three times a day
- Clonazepam: Safety has not been established in children
- Diazepam: Start at 1 mg two to four times a day, and increase gradually as needed/tolerated
- Lorazepam: Safety has not been established in children
- Oxazepam: Safety has not been established for children under 6 years of age. No guideline has been established for children between 6 and 12 years of age. For children over 12 years of age, use 10-15 mg three to four times a day
RENAL
- Chlordiazepoxide: Dose adjustment may be needed in children with renal impairment.
- Diazepam: No dose adjustment needed
- Oxazepam: No dose adjustment needed
ADVERSE DRUG REACTIONS
GENERAL
- Most benzodiazepines can cause these side effects due to their inhibitory effects on brain neurotransmission:
- Anterograde amnesia
- Confusion
- Dizziness
- Depression
- Sedation
- Withdrawal symptoms from benzodiazepines (seizures, hallucinations, agitation, tremors) are most common when using benzodiazepines with shorter half-lives
COMMON
- Alprazolam: Changes in appetite (decrease or increase), weight gain, reduced mucosal production leading to xerostomia and constipation, confusion, sedation, cognitive impairment, memory impairment, irritability
- Chlordiazepoxide: Edema, constipation, nausea, confusion, sedation, cognitive impairment, memory impairment, irritability
- Clonazepam: Depression, ataxia, dizziness, confusion, sedation, cognitive impairment, memory impairment, irritability, upper respiratory infection, respiratory depression
- Diazepam: Hypotension, ataxia, dizziness, confusion, sedation, cognitive impairment
- Lorazepam: Depression, ataxia, dizziness, confusion, sedation, cognitive impairment
- Oxazepam: Dizziness, headache, sedation
OCCASIONAL
- Alprazolam: Decreased libido
- Chlordiazepoxide: Irregular menses, decreased libido
- Clonazepam: Suicidal ideation
- Diazepam: Muscle weakness, respiratory depression; rash and diarrhea can occur with rectal gel use
- Lorazepam: Delirium (especially in elderly patients), weakness
RARE
- Alprazolam: Stevens-Johnson Syndrome, liver failure
- Chlordiazepoxide: Agranulocytosis, liver failure
- Diazepam: Neutropenia
- Lorazepam: Acidosis
DRUG INTERACTIONS
- Benzodiazepine and alcohol can have a synergistic interaction, leading to CNS depression and death.
- + = Contraindication
- This list is not all-inclusive. Please refer to standard drug information resources to check for specific interactions.
Drug-to-Drug Interactions | ||
Drug | Effect of Interaction | Recommendations/Comments |
Alprazolam – boceprevir (Victrelis) | Increased levels of alprazolam | Adjust dose of alprazolam as needed |
Alprazolam – carbamazepine (Tegretol) | Reduced levels of alprazolam | Adjust dose of alprazolam as needed |
Clonazepam – carbamazepine (Tegretol) | Reduced levels of clonazepam | Adjust dose of clonazepam as needed |
Alprazolam – clarithromycin (Biaxin) | Increased levels of alprazolam | Adjust dose of alprazolam as needed |
Alprazolam – cobicistat (Stribild) | Increased levels of alprazolam | Adjust dose of alprazolam as needed |
Alprazolam – delavirdine (Rescriptor)+ | Increased levels of alprazolam | Avoid use If necessary, adjust dose of alprazolam as needed |
Alprazolam, diazepam – digoxin (Lanoxin) | Increased levels of digoxin | Monitor levels of digoxin, and reduce dose as needed |
Diazepam – disulfiram (Antabuse) | Increased levels of diazepam | Adjust dose of diazepam as needed, or change to a benzodiazepine eliminated by glucuronidation |
Diazepam – etravirine (Intelence) | Increased levels of diazepam | Adjust dose of diazepam as needed |
Alprazolam – fluvoxamine (Luvox) | Increased levels of alprazolam | Reduce starting dose of alprazolam by 50%; adjust dose further as needed |
Diazepam - fluvoxamine (Luvox) | Increased levels of diazepam | Adjust dose of diazepam as needed, or change to a benzodiazepine eliminated by glucuronidation |
Alprazolam, diazepam – Fosamprenavir (Lexiva) | Increased levels of benzodiazepine | Adjust dose of benzodiazepine as needed |
Alprazolam – indinavir (Crixivan)+ | Increased levels of alprazolam | Avoid use If necessary, adjust dose of alprazolam as needed |
Alprazolam – itraconazole (Sporanox)+ | Increased levels of alprazolam | Avoid use If necessary, adjust dose of alprazolam as needed |
Diazepam - itraconazole (Sporanox) | Increased levels of diazepam | Adjust dose of diazepam as needed |
Alprazolam – ketoconazole+ | Increased levels of alprazolam | Avoid use If necessary, adjust dose of alprazolam as needed |
Chlordiazepoxide, clonazepam – ketoconazole | Increased levels of benzodiazepine | Adjust dose of benzodiazepine as needed |
Diazepam, lorazepam – olanzapine (Zyprexa) | Increased risk of cardiorespiratory depression | Avoid use of parenteral benzodiazepines and IM olanzapine |
Diazepam – phenyton (Dilantin), fosphenytoin (Cerebyx) | Reduced levels of phenytoin | Monitor phenytoin levels, and adjust dose as needed |
Lorazepam - probenecid | Increased levels of lorazepam | Reduce lorazepam starting dose by 50%; adjust dose further as needed |
Alprazolam, clonazepam, diazepam – ritonavir (Norvir) | Increased levels of benzodiazepine | Adjust dose of benzodiazepine as needed |
Alprazolam, diazepam – saquinavir (Invirase) | Increased levels of benzodiazepine | Adjust dose of benzodiazepine as needed |
Alprazolam – telaprevir (Incivek) | Increased levels of alprazolam | Adjust dose of alprazolam as needed |
Lorazepam – valproate (Depakote) | Increased levels of lorazepam | Reduce lorazepam starting dose by 50%; adjust dose further as needed |
General Precautions: | ||
CNS Depressants | Increased sedative/CNS depressant effects | Monitor for sedative effects, and adjust dose of one or both as needed |
Clozapine (Clozari) | Increased sedative/CNS depressant effects | Decrease dose of benzodiazepine Monitor for increased sedative/CNS depressant effects |
Hydrocodone (Lortab) | Increased sedative/CNS depressant effects | Reduce hydrocodone dose ~25% |
Methadone | Increased sedative/CNS depressant effects | Monitor for sedative effects, and adjust dose of one or both as needed |
Sodium oxybate (Xyrem) | Increased sedative/CNS depressant effects | Monitor for sedative effects, and adjust dose of one or both as needed |
Tapentadol (Nucynta) | Increased sedative/CNS depressant effects | Start tapentadol at 1/3 to 1/2 the usual starting dose |
Zolpidem (Ambien) | Increased sedative/CNS depressant effects | Monitor for sedative effects, and adjust dose of one or both as needed |
PHARMACOKINETIC
Absorption
- Alprazolam[4]: Well-absorbed orally; bioavailability 90%; time to peak concentration 1-2 hours (intermediate)
- Chlordiazepoxide[5]: Well-absorbed orally; time to peak concentration several hours (intermediate)
- Clonazepam[6]: Well-absorbed orally; bioavailability 90%; time to peak concentration 1-4 hours (intermediate)
- Diazepam: Well-absorbed orally; bioavailability 90%; time to peak concentration 0.5-6 hours (rapid)
- Lorazepam: Well-absorbed orally; bioavailability 90%; time to peak concentration 1-2 hours (intermediate)
- Oxazepam[7][8]: Well-absorbed orally; bioavailability 93%; Time to peak concentration 3 hours (intermediate – slow)
Protein Binding
- Alprazolam: 80%
- Chlordiazepoxide: 96%
- Clonazepam: 85%
- Diazepam: 95-98%
- Lorazepam: 85-91%
- Oxazepam: 94-97%
Distribution
- Alprazolam: 0.8-1.3 L/kg
- Chlordiazepoxide: 0.25-0.5 L/kg
- Clonazepam: 1.5-4.4 L/kg
- Diazepam: 1 L/kg
- Lorazepam: 1.3 L/kg
- Oxazepam: 0.59 L/kg
Metabolism
- Alprazolam: Metabolized by the liver (CYP3A4). Excreted primary by kidneys and some via feces
- Chlordiazepoxide: Metabolized by the liver and excreted primary by kidneys
- Clonazepam: Metabolized by the liver (CYP3A4: oxidation and reduction) and excreted primary by kidneys
- Diazepam: Metabolized by the liver (CYP2C19 and CYP3A4: glucuronidation, methylation, oxidation, and hydroxylation) and excreted primary by kidneys
- Lorazepam: Metabolized by the liver (glucuronidation). Excreted primary by kidneys and some via feces
- Oxazepam: Metabolized by the liver and excreted primary by kidneys
Half Life
- Alprazolam: 12-15 hours
- Chlordiazepoxide: 24-48 hours
- Clonazepam: 18-50 hours
- Diazepam: 20-80 hours
- Lorazepam: 10-20 hours
- Oxazepam: 5-11 hours
COMMENTS
- Benzodiazepines are often used to “bridge” patients who are starting an "antidepressant" for anxiety, since the therapeutic effects may be delayed, and patients may experience stimulating side effects initially.
- Benzodiazepines may be more effective than antidepressants for social anxiety disorder[9][10].
- Although beneficial for the acute relief of anxiety, long-term use of benzodiazepines is not recommended due to the risk of dependence. Although tolerance to the anxiolytic effects is uncommon, avoid use in patients with a history of substance use disorder. The risk of dependence is increased with the agents that are rapidly absorbed and with shorter half-lives, i.e., alprazolam and diazepam.
- Benzodiazepines may be beneficial for long-term use in refractory cases.
- One may preferably choose lorazepam or oxazepam: both are metabolized through conjugation and do not produce active metabolites (fewer CYP 450 drug interactions).
References
- Nemeroff CB. Anxiolytics: past, present, and future agents. J Clin Psychiatry. 2003;64 Suppl 3:3-6. [PMID:12662127]
- Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65 Suppl 5:7-12. [PMID:15078112]
- Bellantuono C, Tofani S, Di Sciascio G, et al. Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. Gen Hosp Psychiatry. 2013;35(1):3-8. [PMID:23044244]
- Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet. 1993;24(6):453-71. [PMID:8513649]
- Greenblatt DJ, Shader RI, MacLeod SM, et al. Clinical pharmacokinetics of chlordiazepoxide. Clin Pharmacokinet. 1978;3(5):381-94. [PMID:359214]
- Berlin A, Dahlström H. Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol. 1975;9(2-3):155-9. [PMID:1233263]
- Boudinot FD, Homon CA, Jusko WJ, et al. Protein binding of oxazepam and its glucuronide conjugates to human albumin. Biochem Pharmacol. 1985;34(12):2115-21. [PMID:4004929]
- Sonne J, Loft S, Døssing M, et al. Bioavailability and pharmacokinetics of oxazepam. Eur J Clin Pharmacol. 1988;35(4):385-9. [PMID:3197746]
- Offidani E, Guidi J, Tomba E, et al. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom. 2013;82(6):355-62. [PMID:24061211]
- Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65 Suppl 5:29-33. [PMID:15078116]
To view other topics, please log in or purchase a subscription.
Official website of the Johns Hopkins Antibiotic (ABX), HIV, Diabetes, and Psychiatry Guides, powered by Unbound Medicine. Johns Hopkins Guide App for iOS, iPhone, iPad, and Android included. Complete Product Information.
