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Benzodiazepine Withdrawal

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.

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Benzodiazepine Withdrawal

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

  2. Objectives • History • Epidemiology • Physiology • Treatment

  3. History • Benzodiazepines are “new” drugs • Structure discovered in the 1930s • Activity defined in 1957 • Chlordiazepoxide marketed in the UK in 1960

  4. Annual USA ER Visits • D.A.W.N. Data • 2004: 143,546 • 2005: 189,704 • 2006: 195,625 • 2007: 218,640 • 2008: 271,698

  5. 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 BenzodiazepineDependence. Addiction 1994;89:1535-1541

  6. Kan CC, et al • Present year dependence rates • 40% in general practice patients • 63% in psychiatric out-patients • 82% in self help patients

  7. 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

  8. Physiology • The GABAA channel • Comprised of 5 subunits • 2 α subunits • 2 β subunits • 1 γ subunit

  9. Allosteric Interactions

  10. 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

  11. 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

  12. GABA Effects of Withdrawal

  13. 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

  14. Excitatory Amino Acid Effects of Withdrawal

  15. 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

  16. Total Glutamate Receptor Protein cytosol membrane enriched

  17. 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.

  18. Voltage Dependent Ca2+ Channels

  19. 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

  20. Syndrome • Poorly described • Time course dependent on drug • Generally resembles alcohol withdrawal • Felt to be relatively mild

  21. 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

  22. Tex Med 1990;86:44 • Alprazolam 1 mg QID for years • Abrupt discontinuation 4 days earlier • Hypertensive, tachycardic, febrile • Lorazepam 2 mg (no response)

  23. Continued • Haloperidol 20 mg over 24 hours • Seizure, hypertension, • Oxazepam, metoprolol, alprazolam • Seizure cardiac arrest, death

  24. Treatment • Human • No RCT • Few uncontrolled trials • No large case series • Limited animal data

  25. Gradual dose reduction +/- • Psychotherapy • Buspirone, SSRIs, TCAs • BB blockers, Carbamazepine, Tiagabine, valproate • Aspartate, melatonin

  26. Acute Withdrawal • Exclude life-threatening illness • Fluid and electrolyte managent • Benzodiazepine replacement • Expect large dose requirements • Gentle taper

  27. Delirium • Above plus • Temperature control • Barbiturates, propofol, others • Avoid neuroleptics • Airway management / NMB • Consider calcium channel blocker

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