Benzodiazepine Withdrawal

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Benzodiazepine Withdrawal Robert S. Hoffman, MD Director, NYC Poison Center

description

Benzodiazepine Withdrawal. Robert S. Hoffman, MD Director, NYC Poison Center. Objectives. History Epidemiology Physiology Treatment. History. Benzodiazepines are “new” drugs Structure discovered in the 1930s Activity defined in 1957 Chlordiazepoxide marketed in the UK in 1960. - PowerPoint PPT Presentation

Transcript of Benzodiazepine Withdrawal

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Benzodiazepine Withdrawal

Robert S. Hoffman, MDDirector, NYC Poison Center

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Objectives

History

Epidemiology

Physiology

Treatment

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History

Benzodiazepines are “new” drugs

Structure discovered in the 1930s

Activity defined in 1957

Chlordiazepoxide marketed in the UK in 1960

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Annual USA ER Visits

D.A.W.N. Data

2004: 143,546

2005: 189,704

2006: 195,625

2007: 218,640

2008: 271,698

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Epidemiology

Life time use: 10-15% of men and women

Chronic use USA: approximately 2% Denis C, et al: Pharmacological interventions for

benzodiazepine mono-dependence management in outpatient settings (Review). Cochrane 2009

1.2 million chronic users in the UK Ashton HC: The Treatment of Benzodiazepine

Dependence. Addiction 1994;89:1535-1541

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Present year dependence rates

40% in general practice patients

63% in psychiatric out-patients

82% in self help patients

Kan CC, et al

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Dependence

10,861 patients of the Innsbruck University Department of Psychiatry

WHO criteria were used for the diagnosis of dependence.

Only 9 inpatients and 21 outpatients were addicted to BZs.

Fleischhacker: Acta Psychiatrica Scand 2007;74:80

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Physiology

The GABAA channel

Comprised of 5 subunits

2 α subunits

2 β subunits

1 γ subunit

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Allosteric Interactions

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Two Central Bz Receptors Both increase Cl conductance Differ in location and effect

BZ1 (ω1) Sensory and motor area Sedative, hypnotic

BZ2 (ω2) Subcortical and limbic areas Anxiolytic, anticonvulsant

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BZ Receptor Requirements

γ subunit required to recognize benzodiazepines

α subunits define the receptor type

BZ1 receptor has α1 isoform

BZ2 receptors have the α2, α3 or α5 isoforms

α4 confers resistance to benzodiazepines

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GABA Effects of Withdrawal

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Net Result on GABAA

General resistance to benzodiazepines caused by a change in receptor subunit conformation

Shift toward BZ2 receptor – tolerance to sedation with some maintenance of anticonvulsant effects

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Excitatory Amino Acid Effects of

Withdrawal

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Song J, et al. Benzodiazepine withdrawal-induced glutamatergic plasticity involves up-regulation of GluR1-containing alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in Hippocampal CA1 neurons. J Pharmacol Exp Ther. 2007;322:569-81.

Hippocampal neuron

AMPA current

Glutamate current density

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Total Glutamate Receptor Protein

cytosol membrane enriched

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Xiang K, Tietz EI: Benzodiazepine-induced hippocampal CA1 neuron alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid (AMPA) receptor plasticity linked to severity of withdrawal anxiety: differential role of voltage-gated calcium channels and N-methyl-D-aspartic acid receptors. Behav Pharmacol. 2007;18:447-60.

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Voltage Dependent Ca2+

Channels

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Summary

Decreased sensitivity of GABAA

Change in receptor confirmation

Increased sensitivity of Glutamate

Change in AMPA receptor number and function

Upregulation of L-type (voltage dependent Ca2+ channels

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Syndrome

Poorly described

Time course dependent on drug

Generally resembles alcohol withdrawal

Felt to be relatively mild

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Diazepam 10 mg q6h x years 10 days earlier diazepam discontinued

alprazolam substituted

Bizarre behavior, hallucinations agitation

BP: 215/125 mm Hg

Pulse 130/min

Seizures, elevated temperature

Given haloperidol

Cyanotic cardiac arrest

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Tex Med 1990;86:44

Alprazolam 1 mg QID for years

Abrupt discontinuation 4 days earlier

Hypertensive, tachycardic, febrile

Lorazepam 2 mg (no response)

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Continued

Haloperidol 20 mg over 24 hours

Seizure, hypertension,

Oxazepam, metoprolol, alprazolam

Seizure cardiac arrest, death

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Treatment

Human

No RCT

Few uncontrolled trials

No large case series

Limited animal data

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Gradual dose reduction +/- Psychotherapy Buspirone, SSRIs, TCAs BB blockers, Carbamazepine,

Tiagabine, valproate Aspartate, melatonin

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Acute Withdrawal

Exclude life-threatening illness

Fluid and electrolyte managent

Benzodiazepine replacement

Expect large dose requirements

Gentle taper

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Delirium

Above plus

Temperature control

Barbiturates, propofol, others

Avoid neuroleptics

Airway management / NMB

Consider calcium channel blocker