pharmacotherapy: a review of benzodiazepines• alcohol withdrawal • chlordiazepoxide,...

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Pharmacotherapy: A Review of Benzodiazepines

By: Shaun Gutstein, PharmD

August 13th & 14th, 2019

Conflict of Interest and Disclosures of Relevant Financial

Relationships

The planners and presenters (spouse/domestic partner) of this educational activity have disclosed no healthcare related conflicts of interest, commercial interest, or have any related financial relationships/support.

The material in this presentation is for informational and educational purposes only and is not a substitute for medical advice, diagnosis, or treatment provided by a qualified health care provider. All information contained in this presentation is protected by copyright and remains the property of ProCare HospiceCare. All rights are reserved.

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Contact Hours: Nursing1.0 Contact Hour

ProCare HospiceCare is accredited as a provider of

continuing nursing education by the American Nurses

Credentialing Center’s Commission on Accreditation.

(P-0544, 3/31/2021)

Successful Completion Criteria

• Register for theactivity

• Complete and submitthe sign in sheet

• View the entirepresentation

• Complete and submitthe participantevaluation

• Certificate will beemailed uponcompletion of thecriteria


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Objectives

1. Review the pharmacology of benzodiazepinesavailable in the United States

2. Examine the various uses of benzodiazepines inthe hospice setting, including whenbenzodiazepine use may not be appropriate

3. Calculate equivalent benzodiazepine doses

History

1955: Hoffmann-La Roche chemist, Dr. Leo Sternbach,identified the 1st benzodiazepine: chlordiazepoxide(Librium®)

1963: Diazepam (Valium) was developed

1970s: Benzodiazepines topped most frequentlyprescribed lists as popularity skyrocketed due to aperception of improved safety over barbiturates

Today: 14 unique benzodiazepines are approved bythe U.S. Food and Drug Administration (FDA)

Wick J. Consult Pharm. 2013.

Dr. Leo Sternback, Hoffman-La Roche lab


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Benzodiazepines

Generic Name Brand Name (s)Approximate Dose Equivalence (mg)

Alprazolam Xanax; Xanax XR; Alprazolam Intensol 0.5

Chlordiazepoxide Librium 10

Clobazam Onfi; Sympazan N/A

Clonazepam Klonopin 0.25

Clorazepate Tranxene 7.5

Diazepam Valium; Diastat; Diazepam Intensol 5

Estazolam ProSom N/A

Flurazepam Dalmane 30

Lorazepam Ativan; Ativan Intensol 1

Midazolam Versed 2

Oxazepam Serax 15

Quazepam Doral N/A

Temazepam Restoril 30

Triazolam Halcion 0.25

Lexicomp. 2019.

Mechanism of Action (MoA)


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Indications

• Insomnia• Estazolam, Flurazepam, Quazepam, Temazepam, Triazolam

• Anxiety• Alprazolam, Chlordiazepoxide, Clorazepate, Diazepam, Lorazepam, Midazolam, Oxazepam

• Panic disorders• Alprazolam, Clonazepam

• Seizures• Clobazam, Clonazepam, Clorazepate, Diazepam, Lorazepam

• Muscle relaxant• Diazepam

• Alcohol withdrawal• Chlordiazepoxide, Clorazepate, Diazepam, Oxazepam

• Anesthesia• Lorazepam, Midazolam

Lexicomp. 2019.

Pharmacokinetics: Half-Life (t1/2)Benzodiazepine Parent t1/2 (hours) Active Metabolites (Max t1/2) Factors Extending t1/2

Short-Acting

Triazolam 1.5 – 5.5 Yes (5.5) Liver, Kidney, Age, DDI

Midazolam 1.8 - 6.8 Yes (6.8) Liver, Kidney, Obesity, Age, DDI

Intermediate-Acting

Oxazepam 6 – 11 No Liver, Kidney, Age, Females

Lorazepam 12 – 18 No Liver, RoA

Temazepam 3.5 – 18.4 No Liver

Estazolam 10 – 24 No Liver, DDI

Alprazolam 6.3 - 26.9 Negligible Liver, Obesity, Age, DDI

Clonazepam 17 – 60 No Liver

Long-Acting

Clorazepate Negligible Yes (160) Liver, Kidney, DDI

Flurazepam 2.5 Yes (160) Liver, Kidney, Age

Clobazam 36 – 42 Yes (82) Liver, Kidney, DDI, Age, Race

Chlordiazepoxide 24 - 48 Yes (95) Liver

Quazepam 39 Yes (73) Liver, Kidney, DDI, Age

Diazepam 44 - 72 Yes (174) Liver, Kidney, Age, DDI, RoA

DDI: Drug-Drug Interaction; RoA: Route of AdministrationLexicomp. 2019.


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Relation of Half-Life to Clinical Indications of Benzodiazepines

• Generalized anxiety disorder (GAD)• Post-traumatic stress disorder, chronic (PTSD)

LongLong

• Post-traumatic stress disorder, acute• Panic disorder• Atypical anxiety disorder

IntermediateIntermediate

• Insomnia• Premedication for anesthesia• Atypical anxiety disorder• Panic disorder

ShortShort

Warnings/ Precautions

Black Box Warning:Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of these drugs for use 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.

A retrospective study by the University of Pittsburgh School of Pharmacyshowed a 5-fold increase in the risk of opioid-related overdose during theinitial 90 days and an increase of 1.87 times on days 91 to 180

Estimated that more than 30% of opioid overdoses involve benzodiazepines

Initiate benzodiazepine (or opioid) at a lower doses (e.g. 20-50% dosereduction) and titrate based on response and tolerability

Hernandez I. JAMA. 2018.U.S. Food and Drug Administration. 2016.

National Institute on Drug Abuse. 2018.


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Side Effect Profile

Central Nervous Systemo Depressant (drowsiness,

sedation, confusion, alteredstatus)

o Anterograde amnesia

o Paradoxical reactions

Gastrointestinalo Constipation

o Changes in appetite

o Xerostomia

Cardiovascularo Hypotension

Genitourinaryo Changes in urination

patterns (retention)

Ophthalmico Visual disturbance

Lexicomp. 2019.

American Geriatrics Society Beers Criteria

Tool to improve medication safety in older adults

All benzodiazepines increase risk of cognitive impairment, delirium,falls, and fractures

Older adults have increased sensitivity to benzodiazepines anddecreased metabolism of long-acting agents

Long-acting agents may be appropriate for seizure disorders, rapid eyemovement sleep disorders, benzodiazepine withdrawal, ethanolwithdrawal, severe generalized anxiety disorder, and periproceduralanesthesia in older adults

Short-acting agents (classified by AGS): Alprazolam, Estazolam,Lorazepam, Oxazepam, Temazepam, Triazolam

American Geriatrics Society 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2015.


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Drug Interactions

CYP3A4

Alprazolam

Chlordiazepoxide

Clobazam

Clorazepate

Diazepam

Estazolam

Midazolam

Quazepam

Triazolam

CYP2C9

Clobazam

Clorazepate

Diazepam

Quazepam

Barbie'S Car Goes Real Phast:

o CYP Inducers Barbiturates

Smoking/ St. John’s Wort

Carbamazepine

Griseofulvin

Rifampin

Phenytoin

G ♥ PACMAN:o CYP Inhibitors

Grapefruit

Protease Inhibitors

Azole antifungals

Cyclosporine, Cimetidine

Macrolides (not Azithromycin)

Amiodarone

Non-DHP CCBs (Diltiazem and Verapamil)

Lexicomp. 2019.

LOT Benzodiazepines

ALL Benzodiazepines are metabolized by the liver

The ‘LOT’ benzodiazepines are metabolized by direct, rapid conjugation

o L - Lorazepam

o O - Oxazepam

o T – Temazepam

Do not have active metabolites

Half-life remains relatively the same even in the setting of liver disease

Hayes BD. ALiEM. 2013.


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Triazolam (Halcion®)

Available Formulations: tablet ($$-$$$)

Route(s) of Administration: PO

FDA Approved Indications: Insomnia

Off-Label Indications: Dental preprocedural oral sedation

Special Notes: Rapid onset (15-30min) and shorterduration of action/ t1/2 (7 hrs/ up to 5.5hrs)

Triazolam. Lexi-Drugs Online. 2019.

Midazolam (Versed®)

Available Formulations: Solution for injection ($-$$), oral syrup ($$$)

Route(s) of Administration: Solution for injection may be administered IV, IM,Subcut, IN, BUC, or PR

FDA Approved Indications:

o Anesthesia, Preoperative/ procedural sedation/ anxiolysis/ amesia (includingmechanically ventillated patients)

Off-Label Indications:

o Palliative sedation, Status epilepticus (SE)

Intranasal dosing for SE: Midazolam 5mg/mL solution for injection 0.2 mg/kg

o ½ of total dose into each nare, NTE 1mL per nare

o Use of atomizer may reduce pH induced mucosal irritation

Midazolam. Lexi-Drugs Online. 2019.


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Lorazepam (Ativan®)

Available Formulations: tablet ($), oral solution ($$),solution for injection ($)

Route(s) of Administration: PO, SL, BUC, IV, IM, Subcut, PR

FDA Approved Indications: Anxiety, Insomnia due toanxiety, Anesthesia, Status epilepticus

Off-Label Indications: Alcohol withdrawal delirium/syndrome, Chemotherapy-induced nausea/ vomiting,Psychogenic catatonia, Agitation

Lorazepam. Lexi-Drugs Online. 2019.

Temazepam (Restoril®)

Available Formulations: capsule ($)

o Note: 7.5 and 22.5 mg capsules ($$$)

Route(s) of Administration: PO

FDA Approved Indications: Insomnia

Off-Label Indications: N/A

Special Notes: Low potency (30mg Temazepam = 1mgLorazepam); Consider benzodiazepine tolerance

Temazepam. Lexi-Drugs Online. 2019.


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Alprazolam (Xanax®)

Available Formulations: tablet ($), oral-disintegratingtablet ($$$), oral solution ($$$)

Route(s) of Administration: PO, SL, PR

FDA Approved Indications: Anxiety and Panic Disorders

Off-Label Indications: Preoperative anxiety

Alprazolam. Lexi-Drugs Online. 2019.

Clonazepam (Klonopin®)

Available Formulations: tablet ($), oral-disintegrating tablet ($$$)

Route(s) of Administration: PO, SL, PR

FDA Approved Indications: Panic and Seizure Disorders

Off-Label Indications: Bipolar disorder (mixed or mania), Burning mouthsyndrome, Essential Tremor, Restless Leg Syndrome, Tardive dyskinesia, Ticdisorders, REM sleep behavior disorder

Special Notes: One of the most widely studied benzodiazepines for movementdisorders with anxious component due to pharmacokinetic profile

Clonazepam. Lexi-Drugs Online. 2019.


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Diazepam (Valium®)

Available Formulations: tablet ($), oral solution ($$), Solution for injection($), Rectal gel ($$$)

Route(s) of Administration: PO, SL, PR, IV, IM

Oral absorption is more reliable than IM

FDA Approved Indications: Acute alcohol withdrawal, Anxiety, Muscle spasms,Seizure disorders (including Status epilepticus)

Off-Label Indications: Sedation (ICU)

Diazepam. Lexi-Drugs Online. 2019.

Insomnia

Most hypnotic benzodiazepines have rapid absorption and onset of action

o Pharmacokinetic differences can be used to clinical advantage

Sleep onset difficulties or morning sedation: Use short half-life benzodiazepine (e.g. Triazolam)

Sleep maintenance difficulties: Use longer half-life benzodiazepine (e.g. Temazepam)

Although some FDA-approved for insomnia and others for anxiety, they havesimilar pharmacodynamic properties

Ex: May use Lorazepam or Clonazepam

Note: Using multiple benzodiazepines can lead to additive effects rather thandistinct effects on different symptoms

Ex: Using Temazepam + Lorazepam

Buysse DJ. JAMA. 2013.



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Breathlessness

Definition: Subjective experience of breathing discomfort which may be aresult of physiological (e.g. COPD), psychological (e.g. anxiety), andenvironmental factors (e.g. dry air)

o AKA: Dyspnea, shortness of breath, breathing difficulty, labored breathing

o One of the most common symptoms in the last year of life

Mechanism: Anxiolysis, thus relief of breathlessness

o Benzodiazepines have no effect on respiration in normal doses, (slight depressionof ventilation in higher doses)

Cochrane meta-analysis of 214 participants in eight studies that met criteria

o Only patients with COPD and cancer

Simon ST, et. al. Cochrane Database Syst Rev. 2016.

Breathlessness

No evidence for a beneficial effect of benzodiazepines in the relief ofbreathlessness in people with advanced cancer and COPD

o There is a non-significant beneficial effect, but the overall effect size is small

Consider benzodiazepines as 2nd or 3rd line treatment, when opioids and non-pharmacological measures have failed

No differences regarding the type of benzodiazepine, dose, mode andfrequency of administration, and duration of treatment.

Simon ST, et. al. Cochrane Database Syst Rev. 2016.


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Agitation Benzodiazepines act on GABA receptors in the brain producing inhibitory/ sedative effects

o In agitation involving psychosis, benzodiazepines alone may only sedate a patient

Design: Single-center, double-blind, RCT conducted at an acute palliative careunit at MD Anderson Cancer Center

o 93 patients with advanced cancer

Interventions: Placebo + Haloperidol IV vs. Haloperidol IV + Lorazepam IV Results:

o Mean Richmond Agitation and Sedation Scale (RASS) score prior to medicationadministration: 1.6 points

Placebo + Haloperidol: −2.3 points

Lorazepam + Haloperidol group −4.1 points

Required fewer rescue medications

Perceived to be more comfortable by both caregivers and nurses blinded to treatment assignment

No difference in adverse events, respiratory depression, or survival

Hui D, et. al. JAMA. 2017.Wilson MP, et. al. West J Emerg Med. 2012.

Acute Seizures/ Status Epilepticus (SE)

1st Line:o Midazolam IM (10mg for > 40kg, 5mg 13-40kg, single dose) OR

o Lorazepam IV (0.1mg/kg/dose, max 4mg/ dose, may repeat dose once) OR

o Diazepam IV (0.15-0.2mg/kg/dose, max 10mg/ dose, may repeat dose once)

2nd Line:o Diazepam PR (0.2-0.5mg/kg, max 20mg/ dose, single dose) OR

o Midazolam IN or BUC

Difficult to utilize parenteral therapies in the home/ nursing home setting

o Lorazepam 2-4mg PO/SL/PR q5min prn active seizure, NTE 8mg/ episode

o Diazepam 10mg PO/SL/PR, may repeat dose once

o Midazolam IN or BUC

Glauser T, et. al. Epilepsy Curr. 2016.Diazepam. Lexi-Drugs Online. 2019.


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Seizure Maintenance Therapy

Benzodiazepine are useful when the patient is no longer able to utilize oralroute

o Many benzodiazepines may be administered SL or PR (e.g. Lorazepam,Clonazepam)

Minimal history is available

Clonazepam: 1.5 mg given in 3 divided doses; may increase by 0.5 to 1 mgevery 3rd until seizures are controlled or adverse effects seen (max: 20mg/day)

Lorazepam: 0.5 – 2 mg po 2-4 times daily

Clonazepam. Lexi-Drugs Online. 2019.Lorazepam. Lexi-Drugs Online. 2019.

Myoclonus

Diazepam’s skeletal muscle relaxant properties 1st described in initial studiesdating back to its discovery in 1963

Myoclonic action of benzodiazepines is thought to be the enhancement ofGABA neurotransmission via benzodiazepine receptor in brain and spinal cord

o Treatment option for opioid-induced myoclonus

Dosing:

Diazepam 2-10mg po 3-4 times daily

Clonazepam 0.5-6mg/day or greater

Valium®. Roche Laboratories Inc. 2008.Caviness JN. Neurotherapeutics. 2014.


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Nausea and Vomiting

GABA-mediated antiemetic and anxiolytic properties

Proven effective as an adjunct for chemotherapy inducednausea/ vomiting (CINV) and anticipatory nausea/vomiting (ANV)

Lorazepam 0.5 to 2 mg PO/SL/PR/IV q6h prn N/V

Lorazepam. Lexi-Drugs Online. 2019.Berger MJ, et. al. J Natl Compr Canc Netw. 2017.

Palliative Sedation

Use of sedative medications to reduce patients’ consciousness in orderto manage end-of-life symptoms that have become refractory andintolerable

Midazolam is metabolized to a lipophilic compound that rapidlypenetrates the central nervous system and brief duration of action

o Continuous infusion

Dosing: Midazolam continuous IV/ Subcut infusion: Initial: 0.5-1mg/hr

o Usual dosage range: 1 to 20 mg/hr

o May administer loading or intermittent bolus doses

Use of midazolam in this setting should be done in close consult withor by an experienced palliative care provider.

Midazolam. Lexi-Drugs Online. 2019.Cherny NI, et. al. Ann Oncol. 2014.

Maltoni M, et. al. J Clin Oncol. 2012


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Other Uses for End of Life Symptom Management

Hiccups:o Midazolam subcutaneous infusion 10-60mg/24hrs shown effective for

refractory intractable hiccups of peripheral etiology for terminal patient

Restless Leg Syndrome:o Useful to improve sleep and reduce anxiety

o Clonazepam 0.5-1mg po QHS has been studied

Essential Tremor (ET):o Alprazolam 0.125 to 3 mg/day or Clonazepam 0.5 to 6 mg/day showed

symptom improvement in small trials

Carlos K, et. al. Cochrane Database Syst Rev. 2017. Jeon YS, et. al. BMJ Support Palliat Care. 2018.

Zesiewicz TA, et. al. Neurology. 2005.

Discontinuing Benzodiazepines

Rebound/ withdrawal symptoms may occur following abrupt discontinuation orlarge decreases in dose

o Tremorso Anxietyo Perceptual disturbanceso Dysphoriao Psychosiso Seizures

Onset of withdrawal is variableo Period of use, how rapidly use was tapered, pharmacokinetics properties, genetics, use

of Flumazenil

Treatment: Long-acting benzodiazepine (e.g. Clonazepam, Diazepam), titrate toresponse (without adverse effect), then tapered over several months

Alprazolam. Lexi-Drugs Online. 2019.Chang F. CPJ. 2005.


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Discontinuing Benzodiazepines

Strategies for Benzodiazepine Tapering:1. Low-Dose:

o Decrease by 20% each week

2. Direct taper:

o Decrease by 25% the first week, by 25% the second week, then by about 10% everyweek (even slower after prolonged use)

3. Diazepam:

o Convert to short or intermediate t1/2 BDZ at equivalent dose, then taper Decrease by 25% the 1st week, 25% the 2nd week, then by 12.5% every seven days

Start with 50% diazepam dose equivalent & reduce by 10% to 20% daily (5% to 10% if diazepam dose >60 mg)

Decrease diazepam equivalent by 2 mg every 1-2 weeks until 1/2 of initial dose reached, then by 1 mg every 1-2 weeks

4. Alprazolam:

o Decrease by no more than 0.5mg every three days.

o Consider slower taper for patients taking >4 mg/day for 3 months.

Alprazolam. Lexi-Drugs Online. 2019.Chang F. CPJ. 2005.

Flumazenil (Romazicon®)

FDA approved for BDZ reversal and management of overdose

BDZ Receptor Antagonist: Competitively inhibits the activity at thebenzodiazepine receptor site on the GABA/benzodiazepine receptorcomplex

o Does not antagonize effect ethanol, barbiturates, general anesthetics,and opioids

Rapidly acting with short half-life, must be administered repeatedly

May precipitate benzodiazepine withdrawal in patients who arebenzodiazepine dependent

Management of benzodiazepine overdose:

o Usual dosing: 0.2mg IV over 30 sec.; if the desired level of consciousness is not obtained30 sec. after the dose, 0.3mg can be given over 30 sec.

o Repeat doses: 0.5 mg over 30 sec at 1-min intervals, up to 3-5mg

Flumazenil. Lexi-Drugs Online. 2019.



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Converting Benzodiazepines

Benzodiazepine Approximate Dose Equivalence (mg)

Alprazolam 0.5

Clonazepam 0.25

Diazepam 5

Lorazepam 1

Midazolam 2

Temazepam 30

PT is a 98 y.o. taking Diazepam 5mg PO TID. The MD would like to convert PT to Lorazepam. What is the correct dose?

Converting Benzodiazepines

2. Cross multiply

=

=

1. Set up ratio

3. Set up new equation

5 ∗ 15 ∗ 1

4. Solve for X

1 ∗ 15

5

5. Answer

orLorazepam1mgpoTID


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Questions?

Presenter: Shaun Gutstein, PharmD Contact: [email protected]

Coordinator: Suzanne Stewart Contact: [email protected]

References1. Alprazolam. In: Lexi-Drugs Online. New York, NY : Lexi-Comp, Inc.; Updated August 6, 2019; Accessed June 22, 2019.2. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially

Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015; 63(11): 2227-46.3. Benzodiazepine Comparison Table. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. New York, NY. Available at: http://online.lexi.com.

Accessed June 22, 2019.4. Berger MJ, Ettinger DS, Aston J, et. al. NCCN Guidelines Insights: Antiemesis, Version 2.2017. J Natl Compr Canc Netw. 2017; 15(7): 883-893.5. Buysse DJ. Insomnia. JAMA. 2013; 309(7): 706-16. 6. Carlos K, Prado GF, Teixeira CD, et. al. Benzodiazepines for restless legs syndrome. Cochrane Database Syst Rev. 2017; 3: CD006937. Caviness JN. Treatment of Myoclonus. Neurotherapeutics. 2014; 11(1): 188–200.8. Center for Drug Evaluation and Research. New Safety Measures Announced for Opioid Analgesics, Prescription Opioid Cough Products, and

Benzodiazepines. U.S. Food and Drug Administration. https://www.fda.gov/drugs/information-drug-class/new-safety-measures-announced-opioid-analgesics-prescription-opioid-cough-products-and. Published August 31, 2016. Accessed June 22, 2019.

9. Chang F. Strategies for benzodiazepine withdrawal in seniors. CPJ. 2005; 138(8):38-40. 10. Cherny NI, ESMO Guidelines Working Group. ESMO Clinical Practice Guidelines for the management of refractory symptoms at the end of life and

the use of palliative sedation. Ann Oncol. 2014; 25 Suppl 3: iii143-52.11. Clonazepam. In: Lexi-Drugs Online. New York, NY : Lexi-Comp, Inc.; Updated August 5, 2019; Accessed June 22, 2019. 12. Flumazenil. In: Lexi-Drugs Online. New York, NY : Lexi-Comp, Inc.; Updated July 19, 2019; Accessed June 22, 2019.13. Glauser T, Shinnar S, Gloss D, et. al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the

Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016; 16(1): 48-61.14. Hayes BD. Academic Life in Emergency Medicine. All Benzodiazepines are Metabolized by the Liver. Available at:

https://www.aliem.com/2013/11/all-benzodiazepines-are-metabolized-by-the-liver/. Published November 2013. Accessed June 22, 2019.15. Hernandez I, He M, Brooks MM, et. al. Exposure-Response Association Between Concurrent Opioid and Benzodiazepine Use and Risk of Opioid-

Related Overdose in Medicare Part D Beneficiaries. JAMA. 2018; 1(2): e180919.16. Hui D, Frisbee-Hume S, Wilson A. et. al. Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With

Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial. JAMA. 2017; 318(11): 1047-1056.17. Jeon YS, Kearney AM, Baker PG. Management of hiccups in palliative care patients. BMJ Support Palliat Care. 2018; 8(1): 1-18. Lorazepam. In: Lexi-Drugs Online. New York, NY : Lexi-Comp, Inc.; Updated August 7, 2019; Accessed June 22, 2019. 19. Maltoni M, Scarpi E, Rosati M, et. al. Palliative sedation in end-of-life care and survival: a systematic review. J Clin Oncol. 2012; 30(12): 1378-83.20. Midazolam. In: Lexi-Drugs Online. New York, NY : Lexi-Comp, Inc.; Updated August 3, 2019; Accessed June 22, 2019. 21. National Institute on Drug Abuse. Benzodiazepines and Opioids. National Institute on Drug Abuse. https://www.drugabuse.gov/drugs-

abuse/opioids/benzodiazepines-opioids. Published March 15, 2018. Accessed June 22, 2019.22. Simon ST, Higginson IJ, Booth S, et. al. Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in

adults. Cochrane Database Syst Rev. 2016; 10:CD007354.23. Temazepam. In: Lexi-Drugs Online. New York, NY : Lexi-Comp, Inc.; Updated August 6, 2019; Accessed June 22, 2019. 24. Triazolam. In: Lexi-Drugs Online. New York, NY : Lexi-Comp, Inc.; Updated August 6, 2019; Accessed June 22, 2019. 25. Valium(R) [package insert]. Nutley, New Jersey: Roche Laboratories Inc; 2008. 26. Wick J. The History of Benzodiazepines. Consult Pharm. 2013; 28(9): 538-48.27. Wilson MP, Pepper D, Currier GW, et. al. The psychopharmacology of agitation: consensus statement of the American association for emergency

psychiatry project Beta psychopharmacology workgroup. West J Emerg Med. 2012; 13(1): 26-34.28. Zesiewicz TA, Elble R, Louis ED, et. al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the

American Academy of Neurology. Neurology. 2005; 64(12): 2008-20.


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References - Images1. Oransky I. Leo H Sternbach. Lancet. 2005; 366(9495): 1430.

2. Bardal SK, Waechter JE, Martin DS. Chapter 23 - Psychiatry. In: AppliedPharmacology. 1st ed. St. Louis, MO: Elsevier; 2011.


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