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 Benzodiazepine Dependence. Addiction 1994;89:1535-1541

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

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 GABA A 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

17. Net Result on GABA A  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

18. Excitatory Amino Acid Effects of Withdrawal

19. 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

20. Total Glutamate Receptor Protein cytosolmembraneenriched

24. 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.

26. Voltage Dependent Ca 2+ Channels

29. 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 Ca 2+ channels

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

32.  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

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

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

35. Treatment  Human  No RCT  Few uncontrolled trials  No large case series  Limited animal data

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

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

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