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

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

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

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 Copyright Alcohol Medical Scholars Program

AW Pathophysiology: Alcohol and the Brain Variable effects (acute vs. chronic) No single site of action Neurotransmitters affected: Glutamate GABA DA NE CRF Copyright Alcohol Medical Scholars Program

Excitatory Neurotransmission Glutamate/NMDA receptors:  Intracellular calcium (Ca)  neuron excitability Alcohol effects: NMDA receptor antagonist Chronic drinking  tolerance:  NMDA receptors  Ca channels Copyright Alcohol Medical Scholars Program

Excitatory Neurotransmission in AW In rodents, glutamate: Nucleus Accumbens (NAC; reward) Striatum (reward, movement modulation) Hippocampus (memory/mood modulation, seizures) In humans,  CSF glutamate Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

AW and Dopamine DA deficit in NAC  dysphoria/anhedonia Drinking reinstatement   DA  mood During AW delirium: DA and homovanilic acid in CSF Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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) Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

Assessment Optimal Assessment of AW: Complete history, physical, and mental status exam Laboratory test Standardized assessments Copyright Alcohol Medical Scholars Program

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) Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

Benzodiazepines (BZDs) First line agent, best efficacy, safety and cost 6 placebo-controlled trials All are effective: GABAAR function  Seizures: ~ 90%  Delirium: ~ 70% Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program

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. Copyright Alcohol Medical Scholars Program

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 Copyright Alcohol Medical Scholars Program