Alcohol withdrawal

Epidemiology

· 2016 US National Survey on Drug Use and Health, 50% of US adults reported using alcohol at least once in the past 30 days

· According to the CDC, 25.1% of adults > 18 years of age had at least one heavy drinking day (five or more drinks for men and four or more drinks for women) in the past year.

· Alcohol is a significant contributor in up to 40% of all medical admissions and 50% of all surgical Trauma cases

· Alcohol use is associated with 85,000 deaths each year in the US alone

· Approximately half of patients with alcohol use disorder experience alcohol withdrawal when they reduce or stop drinking

· With early identification and appropriate management, mortality from DT is less than 5 percent

Pathophysiology

· Symptoms of alcohol withdrawal occur because alcohol is a central nervous system depressant.

· enhances inhibitory tone (via modulation of gamma-aminobutyric acid [GABA] activity) and inhibits excitatory tone (via modulation of excitatory amino acid activity

· Abrupt cessation unmasks the adaptive responses to chronic ethanol use, resulting in overactivity of the central nervous system.

GABA

· GABA is the major inhibitory neurotransmitter in the brain.

· Highly specific binding sites for ethanol are found on the GABA receptor complex

· As alcohol tolerance develops, the individual retains arousal at alcohol concentrations that would normally produce lethargy or even coma in relatively alcohol-naïve individuals.

· Cessation of alcohol or a reduction from chronically elevated concentrations results in decreased inhibitory tone.

Glutamate

· One of the major excitatory amino acids

· When glutamate binds to the N-methyl-D-aspartate (NMDA) receptor, calcium influx leads to neuronal excitation by binding to the glycine receptor on the NMDA complex

· Ethanol inhibits glutamate-induced excitation. Adaption occurs by increasing the number of glutamate receptors in an attempt to maintain a normal state of arousal.

· Cessation of alcohol or a reduction from chronically elevated concentrations results in unregulated excess excitation.

· Dopamine, also appears to be involved in both alcohol dependence and the manifestations of withdrawal. Increases in dopamine during withdrawal may contribute to hyperarousal

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Symptoms of Alcohol withdrawal

6- 36 hours

Tremors , mild anxiety, headache, diaphoresis, palpitations, anorexia, gastrointestinal upset

Considered Mild withdrawal

6- 48 hours

Single or brief flurry of generalized tonic-clonic seizures, status epilepticus (rare)

Seizures

12 – 48 hours

Visual, auditory, and/or tactile hallucinations with intact orientation and normal vital signs

Alcoholic hallucinations

48 hours – 96 hours and up to 10 days

Delirium, agitation, tachycardia, hypertension, fever, diaphoresis

Delirium Tremens

Symptoms of Alcohol withdrawal

Alcoholic Hallucinations vs Delirium tremens

1) Alcoholic Hallucinations:

· Hallucinations that develop within 12 to 24 hours of abstinence and typically resolve within 24 to 48 hours

· Hallucinations are usually visual, although auditory and tactile phenomena are also described.

2) Delirium Tremens:

· Typically begins between 48 and 96 hours after the last drink and lasts one to five days

Risk Factors for DT :

1. A history of alcohol withdrawal seizures

2. A history of sustained drinking

3. A history of Delirium Tremens (Altered mental status)

4. Age greater than 30

5. presence of a concurrent illness

6. The presence of significant alcohol withdrawal in the presence of an elevated blood alcohol concentration

7. A longer period since the last drink

General Factors to Consider:

• Quantity of alcoholic intake

• Duration of alcohol use

• Time since last drink

• Previous alcohol withdrawals

• Presence of concurrent medical or psychiatric conditions

• Abuse of other agents.

• Should assess possible complicating medical conditions: Arrhythmias, CHF, CAD, gastrointestinal bleeding, infections, liver disease, nervous system impairment, and pancreatitis.

Initial Testing

• Complete blood count

• Liver function tests

• Urine drug screen

• Determination of blood alcohol and electrolyte levels.

CIWA SCORE - Clinical Institute Withdrawal Assessment for Alcohol

• Criteria: N/V, Anxiety, Paroxysmal sweats, Tactile disturbances, Visual disturbances, tremors, agitation, orientation and cloudiness of the sensorium, Auditory disturbances, Headache

Scale for Scoring: Total Score

• 0 – 9: absent or minimal withdrawal

• 10 – 19: mild to moderate withdrawal

• More than 20: severe withdrawal

Management Overview

1) Ruling out alternative diagnoses

• It may be necessary to perform extensive testing, including lumbar puncture and cranial computed tomography (CT), to rule out other diagnostic considerations with confidence

• Especially, Important when the presentation includes altered mental status and fever.

• Factors such as infections, trauma metabolic derangements, drug overdose, hepatic failure, and gastrointestinal bleeding can mimic or coexist with alcohol withdrawal

• A premature diagnosis of alcohol withdrawal can lead to inappropriate use of sedatives, which can further delay accurate diagnosis

2) Supportive Care

• Benzodiazepines are used to control psychomotor agitation and prevent progression to more severe withdrawal

• Supportive care, including intravenous IV fluids, nutritional supplementation, and frequent clinical reassessment including vital signs

• Patients should be placed in a quiet, protective environment.

• Isotonic IV fluid can be infused rapidly until patients are clinically euvolemic

• Thiamine (100 milligrams IV) followed by glucose should be administered in order to prevent or treat Wernicke encephalopathy.

• Multivitamins containing or supplemented with folic acid (Vit B9) should be given routinely, and deficiencies of glucose, potassium, magnesium, and phosphate should be corrected as needed

Wernicke’s Encephalopathy

• Neurologic complication of thiamine (vitamin B1) deficiency

• Thiamine (B1) protects agents oxidative stress

• Thiamine has a role in cerebral energy utilization – Deficiency leads to neuronal injury by inhibiting metabolism in brain regions with high metabolic requirements

• Alcohol leads to reduced absorption as it causes inflammation to the GIT

• Common Symptoms include: Ataxia, confusion, ocular muscle disturbances

Thiamine repletion:

• Neuronal damage occurs usually after 14 days of deficiency (about 20% below normal)

• 200-500mg thiamine IV TID until symptom resolution.

• Replete glucose and magnesium shortly after.

Korsakoff Syndrome

• Usually irreversible condition due to chronic thiamine deficiency resulting in in neuronal death

• Common symptoms: Amnesia, poor recall, confabulation.

• Memory disorder despite appearance of no cognitive losses.

• Recent memory most effected.

• 50% will have permanent impairment after repletion

• Even after thiamine repletion 75% of patients will have some long-term changes – permanent impairment (amnesia).

Benzodiazepines

· Used to treat the psychomotor agitation most patients experience during withdrawal and to prevent progression from minor withdrawal symptoms to major ones

· Diazepam (Valium), lorazepam (Ativan), and chlordiazepoxide (Librium) are used most frequently to treat or prevent alcohol withdrawal, but other benzodiazepines may be used .

· In general, long-acting benzodiazepines with active metabolites (ex, diazepam or chlordiazepoxide) are preferred because they seem to result in a smoother clinical course with lower chance of recurrent withdrawal or seizures

u Lorazepam oral dosing: 2 mg orally every 6 hours for 4 doses, then 1 mg every 6 hours for 8 doses

u Lorazepam IV dosing: 2 to 4 mg IV every 15 to 20 minutes

u Diazepam IV dosing: 5 to 10 mg IV every 5 to 10 minutes

· lorazepam (Ativan) or oxazepam (Serax) are preferred for the treatment of patients with advanced cirrhosis or acute alcoholic hepatitis.

· The shorter half-life of lorazepam and the absence of active metabolites with oxazepam may prevent prolonged effects if over sedation occurs.

· Chlordiazepoxide has a relatively long half-life and may lead to over sedation in patients with severe liver disease

BZD Mechanism of Action

· Positive Allosteric modulators. They bind between Alpha and Gamma subunits

· When BZD are bound, Cl- channel opens longer, which enhances the amount of Cl- entering the cell

· They only work in the presence of GABA. So with prolonged heavy Alcohol use -

u Cross tolerance between BZDs and Alcohol.

3 Strategies:

1) Loading Dose Strategy

· Uses high doses of longer‐acting benzodiazepines to quickly achieve initial sedation with a self‐tapering effect over time due to their pharmacokinetic properties.

· Typically, diazepam 10–20 mg or chlordiazepoxide 100 mg doses are repeated every 1–2 h until the patient reaches adequate sedation with an average of three doses usually required

· Possible Benefits: Reducing the total of BZDs needed, and intense monitoring is usually required in the earlier part

· Possible Drawbacks: Sedation and respiratory depression- need to intensely monitor (especially in elderly patients or those with hepatic dysfunction).

2) Fixed or Scheduled dosing

· Beneficial for patients who will require medication regardless of symptoms, such as in those with a history of seizures or DT

· Also used in patients withdrawing from alcohol with comorbid medical illnesses or if unable to assess withdrawal symptoms.

· Chlordiazepoxide and diazepam remain the agents of choice because of their long‐acting nature

· A ceiling dose of 60 mg of diazepam or 125 mg of chlordiazepoxide is advised per day

After 2–3 d of stabilization of the withdrawal syndrome, the benzodiazepine is gradually tapered off over a period of 7–10 days

3) Symptom Triggered therapy

· Requires regular assessment of patient's withdrawal symptoms using a validated tool like the CIWA scale

· Not applicable in non‐verbal patients

· The cutoff for beginning treatment is a score of at least 8

· 5–10 mg diazepam or 25–100 mg chlordiazepoxide

· If symptoms persist, doses are repeated hourly until the score is below 8.

· Advantages: Lower doses of BZDs used, less sedation, and lower risk of respiratory depression

Barbiturates MOA

· 1. At low doses: They act like BZD (positive allosteric modulators) as they Increase Cl- entry when they bind between the Alpha and Beta subunits.

· 2. At high doses, they can open GABA-A Cl- channels on their own even when GABA is not present.

· 3. Barbiturates can inhibit Glutamate (excitatory) neurotransmitters. Antagonists at the AMPA receptors.

Phenobarbital

· In patients with refractory Delirium tremens or Alcohol withdrawal seizures who require high doses of BZD

· Pts with Chronic heavy Alcohol use who have cross tolerance between Alcohol and BZD

· Phenobarbital Dosing: 130 to 260 mg IV, repeated every 15 to 20 minutes, until symptoms are controlled

Monitoring/ considerations & Precautions

u Do not start benzodiazepines after starting phenobarbital

u Phenobarbital loading doses may need to be reduced in patients with higher risk of sedation or respiratory compromise

u Patients receiving phenobarbital must be on a cardiac monitor with continuous oxygen saturation monitoring

Adverse Effects

Phenobarbital Adverse Effects:

· Somnolence, Syncope, Thrombophlebitis, Megaloblastic anemia, Liver damage, Hypersensitivity reaction, Hallucinations, Angioedema, Respiratory depression

Benzodiazepines Adverse Effects:

· Hypotension, Muscle weakness, Ataxia, Incoordination, Somnolence Euphoria, Respiratory depression, Fatigue

Adjunct Therapy

Dexmedetomidine (Precedex)

· alpha-2 agonist that decreases release of norepinephrine which decreases sympathetic overdrive.

· No controlled trials showing that it prevents the development of seizures or DT. Data so far suggest that may decrease the amount of BZDs used.

· 0.2-1.5 mcg/ kg/ hour

· Adverse Effects: Bradyarrhythmia, Hypotension, Sinus arrest, Tachycardia, Transient hypertension, Hypoxia, Respiratory depression

Clonidine

· Consider in patients with significant increase in blood pressure or nearing hypertensive urgency (pressure > 180/120 mm Hg)

· Other autonomic symptoms such as tachycardia or tremor

· 0.1 mg orally hourly up to 3 times until systolic blood pressure < 140 mm Hg and diastolic pressure < 90 mm Hg

Haloperidol

· For patients exhibiting agitation despite benzodiazepine therapy, giving haloperidol adjunctively can be beneficial.

· Caution is advised because of the potential for a lowering of the seizure threshold, extrapyramidal effects, and risk of QTc prolongation leading to arrhythmias

· Baseline electrocardiogram and electrolyte panel should be obtained, with daily electrocardiograms thereafter

· Suggested haloperidol dosing is 2 to 5 mg intravenously every 0.5 to 2 hours with a maximum dose of 0.5 mg/kg/24 hours

Beta Blockers

• May be considered in combination with benzodiazepines in patients with persistent hypertension or tachycardia, but not used often.

• Atenolol commonly used; typical single doses are50 mg if pulse 50-79 beats/minute or

• 100 mg if pulse ≥ 80 beats/minute

• Common AE: bradycardia, hypotension, fatigue, dizziness, cold extremities, and depression

Prevention and Screening

· Consider prophylactic treatment in inpatients admitted for reasons other than alcohol withdrawal (and are without withdrawal symptoms) and have history of either:

· Withdrawal seizures or delirium tremens

· prolonged, heavy alcohol consumption

· typical prophylactic treatment of hospitalized patients at risk of withdrawal consists of chlordiazepoxide 50-100 mg every 6 hours for 1 day

· reduce to 25-50 mg every 6 hours for 2 additional days

· frequent assessments, and switch to typical treatment regimen if withdrawal symptoms develop

References

Kattimani S, Bharadwaj B. Clinical management of alcohol withdrawal: A systematic review. Ind Psychiatry J. 2013;22(2):100–108. doi:10.4103/0972-6748.132914

J. Biol. Chem. 2012, 287:40224-40231. doi: 10.1074/jbc.R112.386664 originally published online October 4, 2012

Cresce, Nicole D., et al. “Alcohol Withdrawal Syndrome in Medical Patients.” Cleveland Clinic Journal of Medicine, 15 Aug. 2017,

Benzer DG. Management of alcohol intoxication and withdrawal. In: Miller NS, American Society of Addiction Medicine, eds. Principles of Addiction Medicine. Chevy Chase, Md.: The Society; 1994.

https://www.cdc.gov/nchs/fastats/alcohol.htm

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