Appropriate Use of Oral Benzodiazepines
Full update December 2020
Questions often arise regarding the safe prescribing of benzodiazepines. The charts below provide information to help you choose the most appropriate agent and dose based on indication, age, hepatic function, and drug interactions. Prescribing and deprescribing tips are included, as well as patient counseling points. Information in the charts may differ from product labeling.
Benzodiazepine Oral Dosing and Pharmacokinetics
Drug |
Approximate |
Adult Dosing (oral) |
Metabolism |
Alprazolam |
0.5 mg3 |
Anxiety, Panic Immediate release:
|
CYP3A4 to active metabolites (likely clinically insignificant)1 Half-life: |
Bromazepam (Canada) |
3 mg2 |
Anxiety
|
Conjugation2 Half-life: 8 to 30 hours2 |
Chlordiazepoxide |
10 to 25 mg2,3 |
Anxiety
Alcohol
withdrawal |
CYP1A2 to desmethyldiazepam,b then to oxazepam by CYP3A4 and CYP2C19 (minor)1,2,4 Half-life: 100 hours2,d |
Clobazam |
10 mg2 |
Seizures (adjunct)
|
CYP3A4, CYP2C19, and CYP2B6 to active metabolites1 Half-life: |
Clonazepam |
0.25 mg2 |
Seizures
Anxiety: 0.25 to 0.5 mg twice daily2 Panic
|
CYP3A4
to inactive metabolites1 Half-life: |
Clorazepate |
7.5 mg2 |
Anxiety
Alcohol
withdrawal Seizures, adjunct (U.S.)
|
Decarboxylated
in gastrointestinal tract to desmethyldiazepamb (active moiety),
then to oxazepam by CYP3A4 and CYP2C19 (minor).1 Half-life: 100 hours2,d |
Diazepam |
5 mg2 |
Anxiety: 2 to 10 mg two to four times daily. Max total daily dose: 40 mg, divided. Consider a max total daily dose of 5 mg, divided, in the elderly.1 Seizures (adjunct): 2 to 10 mg two to four times daily. Max total daily dose: 40 mg, divided.1 Muscle spasms (adjunct): 2 to 10 mg three to four times daily. Max total daily dose: 40 mg, divided.1,6 Consider a max total daily dose of 5 mg, divided, in the elderly.1 Alcohol withdrawal 10 mg three to four times daily x 24 hours, then 5 mg three to four times daily as needed.6,7 |
CYP3A4, CYP2C9, CYP2C19, and CYP1A2 to desmethyldiazepamb (major), temazepam (minor), and oxazepam (minor)1,2 Half-life: 100 hours2,d |
Estazolam (U.S.) |
1 mg3 |
Insomnia
|
CYP3A4 to active metabolites (likely clinically insignificant)1 Half-life: |
Flurazepam |
15
mg2 |
Insomnia: 15 to 30 mg at bedtime. Consider a max of 15 mg at bedtime in the elderly.1 |
CYP3A4
and CYP2C9 to active metabolites.1,2 Half-life: |
Lorazepam |
1
mg2 |
Anxiety
Insomnia due to anxiety or situational stress: 1 to 4 mg at bedtime as needed.1 Consider a max dose of 1 mg at bedtime as needed in the elderly.1 |
Glucuronidation to inactive metabolite1 Half-life: 9 to 22 hours1 |
Nitrazepam
(Canada) |
5
mg2 |
Insomnia: 2.5 to 10 mg at bedtime (5 mg max in elderly)8 |
CYP2E1
to inactive metabolite.2 Half-life: |
Oxazepam |
15
mg2 |
Anxiety
Alcohol withdrawal: 15 to 30 mg three to four times daily. Elderly may need a lower dose initially.1 |
Glucuronidation to inactive metaboltes1 Half-life: 5 to 15 hours1 |
Quazepam
(U.S.) |
7.5 mg3 |
Insomnia |
CYP3A4 (major) and CYP2C9 and CYP2C19 to active metabolites1 Half-life: 47 to 100 hours1,d |
Temazepam (Restoril, generics) |
15 mg3 |
Insomnia
|
Glucuronidation to inactive metabolites1 Half-life: 8 to 15 hours1 |
Triazolam (Halcion, generics) |
0.25
mg2 |
Insomnia
|
CYP3A4
to inactive metabolites1,2 Half-life: 1.5 to 5.5 hours1 |
- In general, start with the lowest dose in elderly, debilitated, or hepatically impaired patients and increase slowly.1,2
- Desmethyldiazepam: long-acting metabolite responsible at least in part for therapeutic and toxic effects of diazepam, clorazepate, and chlordiazepoxide.3
- For the elderly, and for patients with liver disease, benzos that undergo glucuronidation (lorazepam, oxazepam, temazepam) are preferred over those that undergo oxidative metabolism (e.g., CYP450), especially those with long-acting metabolites: flurazepam, chlordiazepoxide, clorazepate, quazepam, and diazepam.1-3 See our chart, Cytochrome P450 (CYP) Drug Interactions, for help identifying potential drug interactions based on metabolic pathway.
- Includes active metabolite(s).
Preferred
Oral Benzodiazepine per Condition
Benzodiazepines are among the treatment options for several conditions but are not usually the drugs of first choice for chronic use. The chart below addresses preferred benzodiazepines for given conditions when a benzodiazepine might be appropriate.
Condition |
Preferred Benzodiazepine |
Comments |
Alcohol withdrawal |
Chlordiazepoxide, diazepam, lorazepam, or oxazepam.9 See our chart, Outpatient Alcohol Detox and Relapse Prevention, for details to help you choose among them. |
Benzodiazepines are the drugs of choice for management of alcohol withdrawal.9 Parenteral forms of diazepam and lorazepam are available. |
Anxiety |
No agent clearly superior in regard to efficacy.3 Consider agent with medium or long half-life which has been used more extensively for anxiety disorders: clonazepam, lorazepam, or diazepam.3 Shorter acting agents pose higher risk of withdrawal, rebound, and abuse.3,10 |
Ideally, for short-term use only (e.g., for two to six weeks, until antidepressant starts to work, then taper).3 Other roles include treatment of patients who have failed other medications (e.g., SSRI, SNRI, pregabalin), patients who cannot tolerate other medication classes.11 Alprazolam is one of the most abused benzodiazepines; a quick onset leads to euphoria.3 Accounts for one in ten ER visits in U.S. due to drug misuse.12 More toxic in overdose than other benzos.12 Missed doses or discontinuation can cause significant withdrawal quickly.10 May be difficult to taper/discontinue.3 Risk of breakthrough anxiety with immediate-release product.3 Sustained-release product (U.S.) may have less abuse potential.3 Diazepam has fastest onset (<1 hour).2 Diazepam duration of effect shorter than lorazepam despite long half-life; it is lipophilic and quickly redistributes out of the brain.3,13 Consider propranolol for performance anxiety.3 For more information on treatment of anxiety, see our chart, Pharmacotherapy of Anxiety: Beyond the First Line Agents. |
Insomnia |
Temazepam (Restoril, generics) (favorable benefit vs risk).14 |
See our chart, Comparison of Insomnia Treatments (U.S. subscribers; Canadian subscribers), for non-benzodiazepine alternatives. |
Panic attacks |
Clonazepam, lorazepam, or diazepam (most evidence of efficacy).11 |
Benzodiazepines generally not first-line.11 Can use as adjunct to antidepressant to achieve symptom control acutely or to relieve residual anxiety.11 See comments under “Anxiety” regarding alprazolam. |
Low back pain |
Most evidence for diazepam.15 |
See our chart, Muscle Relaxants, for details regarding use. For alternatives, see our charts, Treatment of Acute Low Back Pain and Treatment of Chronic Low Back Pain. |
Tips for Prescribing and Deprescribing
Benzodiazepines
Goal |
Suggested
Strategies or Resources |
Educate patients about benzodiazepine safety. |
In the U.S., benzodiazepines are dispensed with a MedGuide that covers risks.17 Consider these patient counseling points when talking to patients about starting a benzodiazepine:
|
Safely initiate a benzodiazepine. |
Consider all therapeutic options for management of the patient’s condition, and provide information about non-drug alternatives.17 Limit dosages and durations to the minimum required.21 Have an exit plan.23 Some experts suggest follow-up in one to four weeks. Screen for potentially problematic drug interactions (e.g., opioids).19,21 Before prescribing and throughout treatment, assess the patient’s risk of abuse, misuse, and addiction.17 Screening and assessment tools are available at: https://www.drugabuse.gov/nidamed-medical-health-professionals/screening-tools-resources/chart-screening-tools. |
Educate patients about benzodiazepine discontinuation and get patient buy-in. |
First, ask patients what their goals and preferences are regarding their benzodiazepine.16 Involve the caregiver, or care team in a long-term care setting.22 Consider addressing the following benefits of discontinuation:
Regarding the discontinuation process, consider addressing the following points:
Consider
sharing the validated EMPOWER brochure, available at
http://www.criugm.qc.ca/fichier/pdf/BENZOeng.pdf.18 |
Identify patients for whom benzodiazepines should be tapered. |
Patients ≥65 years of age18 Patients <65 years of age who have used a benzo most days of the week for >4 weeks.16 Be aware that case reports describe a
wide range of time to dependence, with some reporting the onset as early as days
to weeks after the start of a benzodiazepine.17 |
Identify strategies for a successful benzodiazepine taper. |
Monitor every one to two weeks.16 Consider an especially slow taper (e.g., at least six to 12 weeks) for patients taking alprazolam; patients taking a high dose (e.g., alprazolam >4 mg/day); patients taking a benzo for >2 to 3 months; and for patients with panic disorder or a seizure disorder.2,11,24 Be prepared to address severe or life-threatening withdrawal reactions include catatonia, seizures, delirium tremens, depression, suicidal or homicidal thoughts, mania, or psychosis.17 Also watch for a protracted withdrawal syndrome that persists beyond initial benzodiazepine withdrawal. Symptoms may last as long as 12 months, and include depression, cognitive impairment, insomnia, anxiety, motor symptoms, paresthesia, or tinnitus.17 In case of worsening of underlying condition or withdrawal symptoms, maintain benzodiazepine dose or increase to the previous step for one to two weeks, then taper more slowly.16,17,22 Incorporate non-drug approaches to manage underlying conditions (e.g., sleep hygiene, cognitive behavioral therapy).16 For patients on both an opioid and benzodiazepine, it may be safer and more practical to taper the opioid first.19 The benzodiazepine may help with opioid withdrawal.19 Depending on patient reliability, consider having the pharmacist dispense only a week’s worth of medication (or less) at a time.26 Provide a written tapering plan to improve chance of success.18 |
Formulate a benzodiazepine tapering plan for your patient. |
There is no one tapering schedule suitable for all patients.17 Suggested tapering regimens include:
Special considerations:
|
Prepared by the Editors of Therapeutic Research Center (361206).
References
- Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2020. http://www.clinicalkey.com. (Accessed November 3, 2020).
- e-CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2020. Benzodiazepines. CPhA monograph (May 2015). http://www.e-therapeutics.ca. (Accessed November 3, 2020).
- Bostwick JR, Gardner KN. Anxiety disorders. In: Zeind CS, Carvalho MG, editors. Applied Therapeutics: The Clinical Use of Drugs. 11th ed. Philadelphia, PA: Wolters Kluwer Health, 2018: 1731-61.
- Mayo Clinic Laboratories. Benzodiazepines. https://www.mayocliniclabs.com/test-info/drug-book/benzodiazepines.html. (Accessed November 3. 2020).
- Product monograph for Teva-bromazepam. Teva Canada. Toronto, CA M1B 2K9. September 2019.
- Product information for Valium. Roche Laboratories. Little Falls, NJ 07424. June 2017.
- Product monograph for Valium. Hoffman-La Roche. Mississauga, ON L5N 5M8. April 2018.
- Product monograph for Mogadon. AA Pharma. Vaighan, ON L4K 4N7. September 2019.
- Clinical Resource, Outpatient Alcohol Detox and Relapse Prevention. Pharmacist’s Letter/Prescriber’s Letter. February 2019.
- Cosci F, Chouinard G. Acute and persistent withdrawal syndroms following discontinuation of psychotropic medications. Psychother Psychosom 2020;89:283-306.
- Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress, and obsessive-compulsive disorders. BMC Psychiatry 2014;14(Suppl 1):S1-83.
- Bush DM. Emergency department visits involving nonmedical use of the anti-anxiety medication alprazolam. SAMHSA. The CBHSQ Report May 22, 2014. https://www.ncbi.nlm.nih.gov/books/NBK384675/pdf/Bookshelf_NBK384675.pdf. (Accessed November 5, 2020).
- Dundee JW, McGowan WA, Lilburn JK, et al. Comparison of the actions of diazepam and lorazepam. Br J Anaesth 1979;51:439-46 [abstract].
- Sateia MJ, Buysse DJ, Krystal AD, et al. 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;13:307-49.
- Van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev 2003;2:CD004252.
- Pottie K, Thompson W, Davies S, et al. Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guidelines. Can Fam Physician 2018;64:339-51.
- FDA Drug Safety Communication. FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. September 23, 2020. https://www.fda.gov/media/142368/download. (Accessed November 5, 2020).
- Tannenbaum C, Martin P, Tamblyn R, et al. Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med 2014;174:890-8.
- Dowell D, Haegerich TM, Chou R. CDC Guideline for prescribing opioids for chronic pain - United States, 2016. MMWR Recomm Rep 2016;65:1-49.
- Chang F. Strategies for benzodiazepine withdrawal in seniors. CPJ 2005;138:38-40.
- Health Canada. Updated to safety labelling for benzodiazepines and benzodiazepine-like drugs. October 30, 2020. https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/74223a-eng.php. (Accessed November 6, 2020).
- Ng BJ, :Le Couteur DG, Hilmer SN. Deprescribing benzodiazepines in older patients: impact of interventions targeting physicians, pharmacists, and patients. Drugs Aging 2018;35:493-521.
- Kaiser Permanente. Benzodiazepine and Z-drug safety guideline. January 2019. https://wa.kaiserpermanente.org/static/pdf/public/guidelines/benzo-zdrug.pdf. (Accessed November 6, 2020).
- Product monograph for Xanax. Upjohn Canada. Kirkland, QC H9J 2M5. May 2020.
- American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. 2nd edition. January 2009. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/panicdisorder.pdf. (Accessed November 9, 2020).
- National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic non-cancer pain. Part B. Recommendations for practice. http://nationalpaincentre.mcmaster.ca/documents/opioid_guideline_part_b_v5_6.pdf. (Accessed November 7, 2020).
Cite this document as follows: Clinical Resource, Appropriate Use of Oral Benzodiazepines. Pharmacist’s Letter/Prescriber’s Letter. December 2020.