Copyright Alcohol Medical Scholars Program 1 ALCOHOL WITHDRAWAL: PATHOPHYSIOLOGY, DIAGNOSIS AND...
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Copyright Alcohol Medical Scholars Progra m 1 ALCOHOL WITHDRAWAL: ALCOHOL WITHDRAWAL: PATHOPHYSIOLOGY, DIAGNOSIS PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT AND TREATMENT Carlos A. Hernandez-Avila, M.D. University of Connecticut School of Medicine Alcohol Medical Scholars Program
Copyright Alcohol Medical Scholars Program 1 ALCOHOL WITHDRAWAL: PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT Carlos A. Hernandez-Avila, M.D. University of
Copyright Alcohol Medical Scholars Program 1 ALCOHOL
WITHDRAWAL: PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT Carlos A.
Hernandez-Avila, M.D. University of Connecticut School of Medicine
Alcohol Medical Scholars Program
Slide 2
Copyright Alcohol Medical Scholars Program 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
Slide 3
Copyright Alcohol Medical Scholars Program 3 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
Slide 4
Copyright Alcohol Medical Scholars Program 4 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
Slide 5
Copyright Alcohol Medical Scholars Program 5 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
Slide 6
Copyright Alcohol Medical Scholars Program 6 Variable effects
(acute vs. chronic) No single site of action Neurotransmitters
affected: Glutamate GABA DA NE CRF AW Pathophysiology: Alcohol and
the Brain
Slide 7
Copyright Alcohol Medical Scholars Program 7 Excitatory
Neurotransmission Glutamate/NMDA receptors: Intracellular calcium
(Ca) neuron excitability Alcohol effects: NMDA receptor antagonist
Chronic drinking tolerance: NMDA receptors Ca channels
Slide 8
Copyright Alcohol Medical Scholars Program 8 Excitatory
Neurotransmission in AW In rodents, glutamate: Nucleus Accumbens
(NAC; reward) Striatum (reward, movement modulation) Hippocampus
(memory/mood modulation, seizures) In humans, CSF glutamate
Slide 9
Copyright Alcohol Medical Scholars Program 9 Inhibitory
Neurotransmission GABA/GABA A - R: Chloride neuron excitability
Alcohol effects: Acute, GABA A - R function Chronic, GABA A - R
sensitivity tolerance During AW: GABA A - R function Repeated AW
kindling AW severity
Slide 10
Copyright Alcohol Medical Scholars Program 10 Dopamine (DA)
Mediates reward: Released by VTA NAC In anticipation / during
reward Alcohol effects: Acute, DA in NAC Chronic, DA in NAC
tolerance
Slide 11
Copyright Alcohol Medical Scholars Program 11 DA deficit in NAC
dysphoria/anhedonia Drinking reinstatement DA mood During AW
delirium: DA and homovanilic acid in CSF AW and Dopamine
Slide 12
Copyright Alcohol Medical Scholars Program 12 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
Slide 13
Copyright Alcohol Medical Scholars Program 13 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
Slide 14
Copyright Alcohol Medical Scholars Program 14 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)
Slide 15
Copyright Alcohol Medical Scholars Program 15 Diagnosis and
Evaluation Begins after few hours/days + distress/impairment Begins
after few hours/days + distress/impairment 2+ of: 2+ of: Autonomic
activity (e.g. sweating or pulse > 100) Hand tremor Insomnia
Nausea or vomiting hallucinations or illusions agitation Anxiety
Grand mal seizures
Slide 16
Copyright Alcohol Medical Scholars Program 16 Assessment
Optimal Assessment of AW: Optimal Assessment of AW: Complete
history, physical, and mental status exam Laboratory test
Standardized assessments
Slide 17
Copyright Alcohol Medical Scholars Program 17 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: Signs of
chronic drinking: General Other (gastrointestinal, neurological,
psychiatric,etc)
Slide 18
Copyright Alcohol Medical Scholars Program 18 Laboratory Tests
Identify acute and/or heavy drinking (> 5 drinks/day): 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
Slide 19
Copyright Alcohol Medical Scholars Program 19 Clinical
Institute Withdrawal Assessment (CIWA-Ar) Standardized assessment
of 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
Slide 20
Copyright Alcohol Medical Scholars Program 20 Course of AW
Stages 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
Slide 21
Copyright Alcohol Medical Scholars Program 21 Treatment Setting
80% ambulatory (O/P): CIWA
Slide 22
Copyright Alcohol Medical Scholars Program 22 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
Slide 23
Copyright Alcohol Medical Scholars Program 23 Benzodiazepines
(BZDs) First line agent, best efficacy, safety and cost 6
placebo-controlled trials All are effective: GABA A R function
Seizures: ~ 90% Delirium: ~ 70%
Slide 24
Copyright Alcohol Medical Scholars Program 24 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
Slide 25
Copyright Alcohol Medical Scholars Program 25 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
Slide 26
Copyright Alcohol Medical Scholars Program 26 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
Slide 27
Copyright Alcohol Medical Scholars Program 27 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
Slide 28
Copyright Alcohol Medical Scholars Program 28 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
Slide 29
Copyright Alcohol Medical Scholars Program 29
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.
Slide 30
Copyright Alcohol Medical Scholars Program 30 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