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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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)

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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

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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

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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

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Copyright Alcohol Medical Scholars Program 21 Treatment Setting 80% ambulatory (O/P): CIWA

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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

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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%

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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

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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

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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

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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

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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

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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.

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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