Transcript bz withdrawal for eapcct 2010

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
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
Kan CC, et al
 Present year dependence rates
 40% in general practice patients
 63% in psychiatric out-patients
 82% in self help patients
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-amino3-hydroxy-5-methylisoxazole-4-propionic acid receptors in
Hippocampal CA1 neurons. J Pharmacol Exp Ther. 2007;322:56981.
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-4propionic 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
2+
Ca 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