Post on 03-Feb-2016
description
Benzodiazepine Withdrawal
Robert S. Hoffman, MDDirector, 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
Annual USA ER Visits
D.A.W.N. Data
2004: 143,546
2005: 189,704
2006: 195,625
2007: 218,640
2008: 271,698
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
Present year dependence rates
40% in general practice patients
63% in psychiatric out-patients
82% in self help patients
Kan CC, et al
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
Physiology
The GABAA channel
Comprised of 5 subunits
2 α subunits
2 β subunits
1 γ subunit
Allosteric Interactions
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
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
GABA Effects of Withdrawal
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
Excitatory Amino Acid Effects of
Withdrawal
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
Total Glutamate Receptor Protein
cytosol membrane enriched
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.
Voltage Dependent Ca2+
Channels
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
Syndrome
Poorly described
Time course dependent on drug
Generally resembles alcohol withdrawal
Felt to be relatively mild
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
Tex Med 1990;86:44
Alprazolam 1 mg QID for years
Abrupt discontinuation 4 days earlier
Hypertensive, tachycardic, febrile
Lorazepam 2 mg (no response)
Continued
Haloperidol 20 mg over 24 hours
Seizure, hypertension,
Oxazepam, metoprolol, alprazolam
Seizure cardiac arrest, death
Treatment
Human
No RCT
Few uncontrolled trials
No large case series
Limited animal data
Gradual dose reduction +/- Psychotherapy Buspirone, SSRIs, TCAs BB blockers, Carbamazepine,
Tiagabine, valproate Aspartate, melatonin
Acute Withdrawal
Exclude life-threatening illness
Fluid and electrolyte managent
Benzodiazepine replacement
Expect large dose requirements
Gentle taper
Delirium
Above plus
Temperature control
Barbiturates, propofol, others
Avoid neuroleptics
Airway management / NMB
Consider calcium channel blocker