ALCOHOL WITHDRAWAL:

PATHOPHYSIOLOGY, DIAGNOSIS
AND TREATMENT

Carlos A. Hernandez-Avila, M.D.

University of Connecticut School of Medicine
Alcohol Medical Scholars Program
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 Introduction
 Alcohol Dependence (AD)→mortality/morbidity
 Alcohol Withdrawal (AW): > 2/3 AD patients
 AW often presents as anxiety and insomnia

 Topics to be covered:
 Epidemiology
 Pathophysiology
 Clinical Picture and Diagnosis
 Treatment

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 Epidemiology Alcohol Use
Disorders

 15.3 million

 13 % men and 4 % women age 18

 30% in primary care / general hospitals

 40% trauma patients, blood alcohol 100 mg/dl

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 Alcohol Use Disorders
 Alcohol Abuse:
 Repetitive problems in 1major life areas

 Alcohol Dependence (3 criteria):

 Tolerance
 Withdrawal
 Amount /  time
 Urges, failure to cut down
 Excessive time drinking
 Activities given up
 Use despite problems

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 Epidemiology of AW

 70 % of AD patients
  Rate in the elderly
 No gender/ethnic differences
 85% mild-to-moderate
 15% severe and complicated:
 Seizures
 Delirium Tremens

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 AW Pathophysiology: Alcohol
and the Brain

 Variable effects (acute vs. chronic)

 No single site of action
 Neurotransmitters affected:

Glutamate NE
GABA CRF
DA

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 Excitatory Neurotransmission

 Glutamate/NMDA receptors:
  Intracellular calcium (Ca)  neuron excitability

 Alcohol effects:
 NMDA receptor antagonist
 Chronic drinking  tolerance:
 NMDA receptors
 Ca channels

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Excitatory Neurotransmission in AW

 In rodents, glutamate:
 Nucleus Accumbens (NAC; reward)
 Striatum (reward, movement modulation)
 Hippocampus (memory/mood modulation, seizures)

 In humans,  CSF glutamate

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Inhibitory Neurotransmission
 GABA/GABAA- R:
  Chloride   neuron excitability

 Alcohol effects:
 Acute,  GABAA- R function
 Chronic,  GABAA- R sensitivity  tolerance

 During AW:
  GABAA- R function
 Repeated AW  “kindling” AW severity

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 Dopamine (DA)

 Mediates reward:
 Released by VTA  NAC
 In anticipation / during reward

 Alcohol effects:
 Acute, DA in NAC
 Chronic,  DA in NAC  tolerance

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 AW and Dopamine

 DA deficit in NAC  dysphoria/anhedonia

 Drinking reinstatement   DA  mood

 During AW delirium:
 DA and homovanilic acid in CSF

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 Other Neurotransmitters

 Norepinephrine and MHPG:

 BP / pulse, tremors, diaphoresis
 2-adrenoreceptor function

 Corticotropin-releasing-factor (CRF):
 CRF levels in CSF and amygdala
 CRFR1 receptor sensitivity

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AW Pathophysiology: Key Issues

 Brain homeostasis:
 Excitatory vs. Inhibitory neurotransmission

 Chronic drinking  neuroadaptation

 Allows brain functioning

 AW  neuroadaptation imbalance
  Neuronal firing  autonomic hyperactivity/seizures/DTs

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 Genetics of AW

 Variable AW risk even drinking similar amounts

 Genetic evidence in AW:

 Rodent lines prone to AW seizures
 In humans, AW seizures/delirium:
A9 allele DA transporter
Short allele 5-HT transporter
A1 allele DRD2 (AW with depression)

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 Diagnosis and Evaluation
 Begins after few hours/days + distress/impairment
 2+ of:
  Autonomic activity (e.g. sweating or pulse > 100)
 Hand tremor
 Insomnia
 Nausea or vomiting
 hallucinations or illusions
 agitation
 Anxiety
 Grand mal seizures

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 Assessment

 Optimal Assessment of AW:

 Complete history, physical, and mental status exam

 Laboratory test

 Standardized assessments

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 History and Physical
 Predictors of AW severity:
 Older age
 Severity drinking/tolerance
 Prior AW (“kindling”)
 Major medical/surgical problems
 Sedative/hypnotic use

 Signs of chronic drinking:

 General
 Other (gastrointestinal, neurological, psychiatric,etc)

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 Laboratory Tests

 Identify acute and/or heavy drinking (> 5 drinks/day):

 Blood Alcohol Levels (BAL)

 Gamma-glutamyltransferase (GGTP > 35 IU/L)

 Carbohydrate Deficient Transferrin (CDT > 20 IU/L)

 Erythrocyte mean corpuscular volume (MCV >91.5 3)

 CDT + GGTP best diagnostic combination

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 Clinical Institute Withdrawal
Assessment (CIWA-Ar)
 Standardized assessment of AW symptoms
 Score 8-10 (mild)
 Score 10-15 (moderate)
 Score > 15 (severe) impending delirium tremens

 Assessments:
 Every 4-8 hours until score < 8-10 for 24 hours

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 Course of AW
Stages Symptoms
 I (24 – 48 hours):  Peak severity at 36 hours
90% of AW seizures
Most cases self-limited
 II (48 – 72 hours):
  Stage I symptoms
 III (72 – 105 hours):
 “Delirium Tremens”

 IV (> 7 days):
 Protracted withdrawal

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 Treatment Setting

 80% ambulatory (O/P):

 CIWA <8 or some with CIWA 8 –15

 No hx. of AW seizures/delirium

 No serious medical/surgical problems

 No serious psychiatric/drug hx.

 Social support

 Supervision/housing available

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 Inpatient (I/P) treatment

 10 -20% of patients:
 CIWA > 15 or CIWA 8 –15 + other criteria

  Severity (seizures / delirium) and  # past AW

 Major medical/surgical problems

 Major psychiatric and/or drug problems

 Poor support, homelessness

 Pregnancy

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 Benzodiazepines (BZDs)

 First line agent, best efficacy, safety and cost

 6 placebo-controlled trials
 All are effective:
 GABAAR function

  Seizures: ~ 90%

  Delirium: ~ 70%

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 Choice of a BZD

 Long half-life (chlordiazepoxide, diazepam):

  Seizures: ~ 58%

  Distress (“smoother detox”)

Shorter half-life (lorazepam, oxazepam)

  Oversedation
 Safer in elderly / liver impairment

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 Fixed Schedule Therapy
 Day 1, one of these Q 6 h:
 Chlorodiazepoxide, 50 – 100 mg
 Diazepam, 10 – 20 mg
 Lorazepam, 2 – 4 mg
 Then dose 20% each day

 Fixed schedules often fail to treat AW

 Treatment should allow:
Individualization
Rapid appropriate dosing

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Symptom-triggered Therapy
 Treatment triggered by severity threshold

 One of these Q1 h when CIWA  8:

 Chlorodiazepoxide, 50 - 100 mg
 Diazepam, 10 - 20 mg
 Lorazepam, 2 - 4 mg

 2 controlled trials vs. fixed schedule:

 Equal efficacy / safety
  Dose / side effects / treatment time

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Carbamazepine and Valproate
 Effective in:
 Mild to moderate AW / protracted AW
 distress and faster return to work
 No abuse potential / alcohol interactions
 No toxicity in 7-day trials

 Limitations:
 Not better than BZDs
  Side effects
  Cost
 Limited data in AW seizures/delirium

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 Other Agents
 Antipsychotics:
  seizures,  agitation
 -Adrenergic antagonists and clonidine:
  Autonomic activity, may hide impending seizures
 Magnesium:
  levels in AW, supplement does not  severity
 Ethyl Alcohol:
 No evidence of efficacy, toxic + expensive

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Nonpharmacological Treatment

 Quiet environment
 Nutrition and hydration:
 Oral thiamine (prevents Wernicke-Korsakoff) / folic acid
 Oral fluids / electrolytes
 Orientation to reality
 Brief interventions / motivate to change
 Referral to AA / relapse prevention tx.

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 Conclusions

 AW common complication in AD patients

 Clinicians must screen for AD / AW

 During AW,  excitatory neurotramsmission

 If untreated AW can be deadly or lead to morbidity

 BZD most effective, safest and cheapest treatment

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