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Substance Withdrawal

Substance Withdrawal. Jay Green Emergency Medicine Resident, PGY-2 February 28, 2008. Outline. Pre-test Substance Withdrawal Cases Alcohol Opioid Benzodiazepine Cocaine Post-test Evidence of a proud father!. Pre-test Q1. What percentage of hospitalized patients are ethanol dependent?

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Substance Withdrawal

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  1. Substance Withdrawal Jay Green Emergency Medicine Resident, PGY-2 February 28, 2008

  2. Outline • Pre-test • Substance Withdrawal Cases • Alcohol • Opioid • Benzodiazepine • Cocaine • Post-test • Evidence of a proud father!

  3. Pre-test Q1 • What percentage of hospitalized patients are ethanol dependent? • 5-10% • 15-20% • 30-40% • >40%

  4. Pre-test Q2 • What is the current mortality from alcohol withdrawal syndrome? • 5% • 7% • <1% • 10%

  5. Pre-test Q3 • Alcohol acts as a/an ______________ on the GABA receptor. • Indirect agonist • Direct agonist • Indirect antagonist • Direct antagonist

  6. Pre-test Q4 • In alcohol withdrawal, which of the following agents is best used in patients at risk for oversedation and those with liver disease? • Diazepam • Lorazepam • Phenytoin • Thiamine

  7. Pre-test Q5 • Which of the following agents is best used for AWS if high doses of benzodiazepines are ineffective? • Carbamazepine • Phenytoin • Ethanol • Phenobarbital

  8. Pre-test Q6 • Symptom-triggered therapy in alcohol withdrawal has been shown to reduce which of the following factors? • Amount of medication used • Duration of treatment • Both A and B • Neither A nor B

  9. Pre-test Q7 • Neuroleptic agents: • Effectively control autonomic instability associated with AWS • Control alcohol-induced seizures • Improve hyperthermia related to AWS • Reduce the seizure threshold

  10. Pre-test Q8 • The use of phenytoin is indicated in which of the following situations? • A patient with AWS and non-alcohol-related seizures • A patient with an AWS • A patient with HTN and tachycardia related to AWS • An intoxicated patient with a history of AWS

  11. Pre-test Q9 • The benzodiazepine of choice for treating benzodiazepine withdrawal is: • Midazolam • Lorazepam • Diazepam • Alprazolam

  12. Pre-test Q10 • ED management of opioid withdrawal consists primarily of: • Benzodiazepines • β-blockers • Supportive care • Methadone

  13. Pre-test Q11 • Patients with acute cocaine withdrawal often require admission. True False

  14. Case 1 • 43M previously healthy, no meds • Unemployed, brought in by sister • N, V today, sister worried about hand tremor • SocHx: Smoker, “few beers”/day x years • O/E • HR 112, bp 160/96 • Appears a bit anxious • Tremulous

  15. Case 2 • 43M no known PMH/meds • Brought in by EMS • Found to be agitated, vomiting, ?hallucinating • Hx from pt unhelpful • O/E • Not oriented, GCS 13 (E4V4M5) • Vitals 130, 175/100, 387, 20, 95% • Volatile, ?visual hallucinations/anxious • ++tremulous, ?hyperreflexia

  16. Alcohol Withdrawal

  17. Alcohol Withdrawal - History • First described by Pliny the Elder, 1st century BC • Naturalis Historia • "...drunkenness brings pallor and sagging cheeks, sore eyes, and trembling hands that spill a full cup, of which the immediate punishment is a haunted sleep and unrestful nights. ..." • Osler • Initial tx • Supportive, KBr, chloral hydrate, hyoscine, opium • Isbell et al, 1955 • Alcohol  withdrawal syndrome • Amount/duration of alcohol intake  severity Isbell H, Frasier HF, Wilkler A et al. An experimental study of the etiology of “rum fits” and delirium tremens. QJ Study Alcohol 1955;16:1.

  18. Alcohol W/D - Epidemiology • 22% of Americans >12y report binge drinking at least once during the past 30d • 7% report heavy regular drinking • 2003 US National Survey on Drug Use and Health • These are the people who actually answer surveys • 15-20% hospitalized pts are alcohol dependent • Hodges and Mazur, Pharmacotherapy 2004;24:1578-85 • Mortality <1%

  19. Alcohol W/D - Pathophysiology • Chronic EtOH  CNS depressant • ↑ GABAminergic tone  sedation via GABAa-receptor • Downregulation of GABAa-receptor • Normal level of consciousness with ↑↑EtOH • NMDA inhibition • Upregulation of NMDA-receptors • W/D of EtOHCNS excitation (↓GABA, ↑NMDA) • Inhibitory control of excitatory NT’s is lost • CNS excitation (tremor, sz, hallucination) • ANS stimulation (HTN, sweating, hyperthermia, tachycardia)

  20. Case 1 • 43M previously healthy, no meds • Unemployed, brought in by sister • N, V today, sister worried about hand tremor • SocHx: Smoker, “few beers”/day x years • O/E • HR 112, bp 160/96 • Appears a bit anxious • Tremulous • What else is on the ddx?

  21. DDx • What else is on the ddx? • Acute psychosis • CNS infection • Thyrotoxicosis • Anticholinergic poisoning • W/D from other sedative-hypnotics

  22. Alcohol W/D - Signs/Symptoms • Do you need to stop EtOH consumption to get EtOH W/D? • When do signs of W/D begin?

  23. Alcohol W/D - Signs/Symptoms • Begin 6-24h after decreasing EtOH • Can occur with continued lower volume EtOH • Lasts 2-7d • Severity  dose/duration of EtOH

  24. Alcohol W/D - Classification • How do you classify EtOH W/D? • 4 stages: • Tremulousness (6-12h) • Hallucinations (12-48h) • Seizures (12-48h) • DT’s (>48h) • Minor  Major  DT’s • Timing & severity • early/late & complicated/uncomplicated

  25. Alcohol W/D - Classification • Minor  Major  DT’s • What are some symptoms of minor W/D? • Early onset, peak 24-36h • N, anorexia, tremor, tachycardia, HTN, hyperreflexia, insomnia, anxiety • What are some symptoms of major W/D? • Later onset (24h), peaks 2-5d • ++anxiety, insomnia, irritability, tremor, anorexia, tachycardia, hyperreflexia, HTN, fever, seizure, auditory/visual hallucinations, delirium

  26. Alcohol Withdrawal - Diagnosis • DSM-IV diagnostic criteria Alcohol Withdrawal • Cessation/reduction of heavy/prolonged alcohol use resulting in the development of two or more of the following: • ANS hyperactivity, increased hand tremor, insomnia, N, V, transient hallucinations, psychomotor agitation, anxiety, sz, affected global function

  27. Alcohol Withdrawal - Diagnosis • DSM-IV diagnostic criteria Alcohol Withdrawal with Delirium (‘DT’s’) • Also includes decreased consciousness, change in cognition, perceptual disturbance

  28. Case 2 revisited • 43M no known PMH/meds • Brought in by EMS • Found to be agitated, vomiting, ?hallucinating • Hx from pt unhelpful • O/E • Not oriented, GCS 13 (E4V4M5) • Vitals 130, 175/100, 387, 20, 95% • Volatile, ?visual hallucinations/anxious • ++tremulous, ?hyperreflexia • You think they have DT’s. • What else is on the ddx?

  29. Case 2 • You think this patient has delirium tremens • What else could this be? • Sepsis • Meningitis • SAH • Heat stroke • Serotonin syndrome • NMS • Cocaine/amphetamine toxicity • Malignant hyperthermia

  30. Alcohol W/D – Delirium Tremens • Extreme end of the spectrum • Almost never before 3d • 5% of pts hospitalized for EtOH W/D • Difficult to predict who will get it • Can last up to 2 weeks • THESE PATIENTS ARE SICK!

  31. Case 2 revisited • 43M no known PMH/meds • Brought in by EMS • Found to be agitated, vomiting, ?hallucinating • Hx from pt unhelpful • O/E • Not oriented, GCS 13 (E4V4M5) • Vitals 130, 175/100, 387, 20, 95% • Volatile, ?visual hallucinations/anxious • ++tremulous, ?hyperreflexia • What investigations?

  32. Alcohol Withdrawal - Ix • C/S • CBC, lytes, BUN, Cr, LFT’s, lipase, INR, EtOH • U/A • CXR • ECG • ±VBG • ±CT head • ±LP • ±Tox screen

  33. Case 2 • Labs sent • ECG – tachycardia • CXR pending • C/S – 2.9 • What would you like to do now?

  34. Case 2 - Tx • Initial Stabilization • ABCs • NGT • ±Restraints • What about giving glucose before thiamine?

  35. Wernicke-Korsakoff Syndrome • Symptoms/signs? • Oculomotor disturbances (nystagmus and ocular palsies), confusion, ataxia – 12% have triad • Mortality 10-20% • Can you precipitate it with glucose administration? • Slovis: “The concept that glucose preceding thiamine in an alcoholic can precipitate Wernicke’s encephalopathy is unfounded/unproven. It is accepted that it takes hours-days for this to occur, and so thiamine given within a reasonable time of glucose administration (minutes-hours) is acceptable.”

  36. Wernicke-Korsakoff Syndrome • Case reports • WK syndrome after prolonged IV glucose administration • BOTTOM LINE • Don’t delay glucose for thiamine Waton et al. Ir J Med Sci 1981 Oct;150(10):301-3

  37. Alcohol Withdrawal - Tx • 4 principles of treatment 1) Evaluate for concurrent illness 2) Restore inhibitory tone to CNS 3) ID/correct lyte/fluid deficiencies 4) Allow pt to recover with the least amount of physical restraint to decrease the risk of hyperthermia and rhabdomyolysis EM Reports 26(16) July 25, 2005

  38. Alcohol Withdrawal - Tx • 4 principles of treatment 1) Evaluate for concurrent illness 2) Restore inhibitory tone to CNS 3) ID/correct lyte/fluid deficiencies 4) Allow pt to recover with the least amount of physical restraint to decrease the risk of hyperthermia and rhabdomyolysis EM Reports 26(16) July 25, 2005

  39. Alcohol Withdrawal - Tx • >150 drug combinations • Benzos are mainstay • Interact with GABAa-receptor • Substitute for removal of EtOH as a GABAa-agonist

  40. GABA-r GABA ZZZZ…. Cl- Cl- Cl- Cl- BZ-r Cl- Hyperpolarized BZ GABAa-R Intracellular Extracellular

  41. Alcohol Withdrawal - Tx • >150 drug combinations • Benzos are mainstay • Interact with GABAa-receptor • Substitute for removal of EtOH as a GABAa-agonist • Reduce DT’s, mortality, duration of W/D • N=574, randomized pts to benzo, antipsychotic, antihistamine, thiamine • Benzo had lowest risk of DT’s and alcohol W/D sz • Antipsychotic increased sz risk • N=229, 2mg IM Ativan ↓ risk of recurrent sz from 24%3% and ↓admission from 42%29% Kaim et al. Am J Psychiatry 1969;125: 1640-1646 Goldfrank's Toxicologic Emergencies - 8th Ed. (2006)

  42. Alcohol Withdrawal - Benzos • Which benzo? • Ideal: quick onset, long t½ • Diazepam • Most rapid time to peak clinical effects • Limits oversedation • Long t½ (↑↑↑ in advanced liver dz) ***?NOT AVAILABLE IN OUR ED*** • Lorazepam • Shorter t½ • Inactive metabolites • Large doses may lead to propylene glycol A/E (hypotension, dysrrhythmias)

  43. Alcohol Withdrawal - Benzos • How much? • Dosing • PO for mild W/D • Diazepam 5-20mg IV q5-10min • Lorazepam 1-4mg IV q5-10min • Goal breathing spontaneously, N vitals, sedated • Slovis • Diazepam 5, 5, 10, 10, 20, 20, 20… • Lorazepam 1, 1, 2, 2, 4, 4, 4… • Can be massive • 2640mg diazepam + 35mg haloperidol over 48h • Mayo-Smith et al, JAMA 1997;278:1-24

  44. Alcohol Withdrawal - Benzos • Do we use fixed-interval dosing or symptom-triggered dosing? • Symptom triggered dosing • Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) • 10 clinical variables, <5min to complete

  45. Br J Addict 1989;84:1353-1357

  46. Alcohol Withdrawal - Benzos • 3 prospective RCT’s supporting symptom-triggered dosing • ↓Total amount of medication • ↓Duration of treatment • ?↓DT’s • Eg: • Oxazepam 37.5mg vs 231.4mg • Duration of treatment 20h vs 63h Manikant et al, Indian J Med Res 1993;98:170-3 Saitz et al, JAMA 1994;272:519-23 Daeppen et al, Arch Int Med 2002;162:1117-21

  47. Alcohol Withdrawal - Benzos • Typically sufficient for prevention of alcohol withdrawal seizures (AWS) • What next if benzo’s not really working? • More benzos? • Phenobarb? • Propofol? • Haldol?

  48. Alcohol Withdrawal – Barbiturates • Effectiveness shown in uncontrolled studies • Mechanism • Directly open GABAa Cl- channels • Phenobarbital 260mg IV over 5min then 130mg IV over 3min q30min prn • Onset 20-40min • A/E: hypoTN, resp depression Mayo-Smith et al, JAMA 1997;278:1-24

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