1. ALCOHOL WITHDRAWAL: PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT
Dr Hicham Al Mawla
Emergency med
EMJ Lebanon

2. 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

3. Alcohol Use Disorders Alcohol Abuse: Alcohol Dependence (3 criteria):
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

4. 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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5. AW Pathophysiology: Alcohol and the Brain
Variable effects (acute vs. chronic)
No single site of action
Neurotransmitters affected:
Glutamate
GABA DA NE
CRF
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6. 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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7. 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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8. 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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9. Dopamine (DA) Mediates reward: Alcohol effects: Released by VTA  NAC
In anticipation / during reward
Alcohol effects:
Acute, DA in NAC
Chronic,  DA in NAC  tolerance
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10. 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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11. 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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12. 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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13. 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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14. 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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15. Assessment Optimal Assessment of AW:
Complete history, physical, and mental status exam
Laboratory test
Standardized assessments
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16. 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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17. 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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18. Clinical Institute Withdrawal Assessment (CIWA-Ar)
Standardized assessment of AW symptoms
Score (mild)
Score (moderate)
Score > 15 (severe) impending delirium tremens
Assessments:
Every 4-8 hours until score < 8-10 for 24 hours
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19. Course of AW Stages Symptoms I (24 – 48 hours):
II (48 – 72 hours):
III (72 – 105 hours):
IV (> 7 days):
Symptoms
Peak severity at 36 hours
90% of AW seizures
Most cases self-limited
 Stage I symptoms
“Delirium Tremens”
Protracted withdrawal
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20. 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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21. 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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22. 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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23. 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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24. 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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25. Symptom-triggered Therapy
Treatment triggered by severity threshold
One of these Q1 h when CIWA  8:
Chlorodiazepoxide, mg
Diazepam, mg
Lorazepam, mg
2 controlled trials vs. fixed schedule:
Equal efficacy / safety
 Dose / side effects / treatment time
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26. 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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27. Other Agents Antipsychotics: Magnesium: Ethyl Alcohol:
 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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28. 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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29. 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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