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Alcohol Withdrawal
Neela Bhajandas, PharmD
Matthew Hinton, PharmD
Paul N. Williams, MD, FACP
image BASICS
DESCRIPTION
Alcohol withdrawal syndrome (AWS) is a spectrum of symptoms that results from abrupt cessation of alcohol in a dependent patient. Symptoms can begin within 5 hours of the last drink and persist for 5 to 10 days, ranging in severity.
EPIDEMIOLOGY
Each year, 8.2 million Americans meet diagnostic criteria for alcohol dependence. Data suggest that 2-9% of patients seen in a family physician's office have alcohol dependence. It is more prevalent among men, whites, Native Americans, younger and unmarried adults, and those with lower socioeconomic status; only 24% of those with dependence are ever treated. <5% of U.S. adults will experience withdrawal, but 8% of hospitalized patients exhibit signs and symptoms of withdrawal
ETIOLOGY AND PATHOPHYSIOLOGY
  • Consumption of alcohol potentiates the effect of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). With chronic alcohol ingestion, this repeated stimulation downregulates the inhibitory effects of GABA.
  • Concurrently, alcohol ingestion inhibits the stimulatory effect of glutamate on the CNS, with chronic alcohol use upregulating excitatory NMDA glutamate receptors.
  • When alcohol is abruptly stopped, the combined effect of a downregulated inhibitory neurotransmitter system (GABA-modulated) and upregulated excitatory neurotransmitter system (glutamatemodulated) results in brain hyperexcitability when no longer suppressed by alcohol; clinically seen as AWS.
Genetics
There is some evidence for a genetic basis of alcohol dependence.
RISK FACTORS
  • High tolerance, prolonged use, high quantities
  • Previous alcohol withdrawal episodes, detoxifications, alcohol withdrawal seizures, and delirium tremens (DTs)
  • Serious medical problems
  • Concomitant benzodiazepine (BZD) dependence
Geriatric Considerations
Elderly dependent on alcohol are more susceptible to withdrawal, and chronic comorbid conditions place them at higher risk of complications from withdrawal.
Pregnancy Considerations
Hospitalization or inpatient detoxification is usually required for treatment of acute alcohol withdrawal.
GENERAL PREVENTION
  • Routinely screen all adults for alcohol misuse (1)[B].
  • Screen with the CAGE or similar questionnaire
    • Feeling the need to Cut down
    • Annoyed by criticism about alcohol use
    • Guilt about drinking/behaviors while intoxicated
    • Eye opener” to quell withdrawal symptoms
    • Useful to detect problematic alcohol use, positive screen is ≥2 “yes” responses.
  • 10-question AUDIT screening test is also useful to identify problem drinking.
  • The “5 A's” is a screening tool used in primary care settings (Assess, Advise, Agree, Assist, Arrange).
COMMONLY ASSOCIATED CONDITIONS
  • General: poor nutrition, electrolyte abnormalities (hyponatremia, hypomagnesemia, hypophosphatemia), thiamine deficiency, and dehydration
  • GI: hepatitis, cirrhosis, varices, GI bleed
  • Heme: splenomegaly, thrombocytopenia, macrocytic anemia
  • Cardiovascular: cardiomyopathy, hypertension, atrial fibrillation, other arrhythmias
  • CNS: trauma, seizure disorder, generalized atrophy, Wernicke-Korsakoff syndrome
  • Peripheral nervous system: neuropathy, myopathy
  • Pulmonary: aspiration pneumonitis or pneumonia; increased risk of anaerobic infections
  • Psychiatric: depression, posttraumatic stress disorder, bipolar disease, polysubstance abuse
image DIAGNOSIS
  • Diagnostic and Statistical Manual of Mental Disorders AWS criteria are diagnosed when ≥2 of the following present within a few hours to several days after the cessation or reduction of heavy and prolonged alcohol ingestion (2)[C]:
    • Autonomic hyperactivity (sweating, tachycardia)
    • Increased hand tremor
    • Insomnia
    • Psychomotor agitation
    • Anxiety
    • Nausea
    • Vomiting
    • Grand mal seizures
    • Transient (visual, auditory, or tactile) hallucinations or illusions
  • Criteria for DTs include ≥2 of the criteria for AWS and disturbances in orientation, memory, attention, awareness, visuospatial ability, or perception
  • These should cause clinically significant distress or impair functioning and not be secondary to an underlying medical condition or mental disorder.
  • There are three stages of AWS:
    • Stage 1 (minor withdrawal; onset 5 to 8 hours after cessation)
      • Mild anxiety, restlessness, and agitation
      • Mild nausea/GI upset and decreased appetite
      • Sleep disturbance
      • Sweating
      • Mild tremulousness
      • Fluctuating tachycardia and hypertension
    • Stage 2 (major withdrawal; onset 24 to 72 hours after cessation)
      • Marked restlessness and agitation
      • Moderate tremulousness with constant eye movements
      • Diaphoresis
      • Nightmares
      • Nausea, vomiting, diarrhea, anorexia
      • Marked tachycardia and hypertension
      • Alcoholic hallucinosis (auditory, tactile, or visual) may have mild confusion but can be reoriented.
    • Stage 3 (DTs; onset 72 to 96 hours after cessation)
      • Fever
      • Severe hypertension, tachycardia
      • Delirium
      • Drenching sweats
      • Marked tremors
      • Persistent hallucinations
    • Alcohol withdrawal-associated seizures are often brief, generalized tonic-clonic seizures, and typically occur 6 to 48 hours after last drink.
PHYSICAL EXAM
Should include assessment of conditions likely to complicate or that are exacerbated by AWS
  • Cardiovascular: arrhythmias, heart failure, coronary artery disease
  • GI: GI bleed, liver disease, pancreatitis
  • Neuro: oculomotor dysfunction, gait ataxia, neuropathy
  • Psych: orientation, memory (may be complicated by hepatic encephalopathy)
  • General: hand tremor (6 to 8 cycles per second), infections
DIFFERENTIAL DIAGNOSIS
  • Cocaine intoxication
  • Opioid, marijuana, and methamphetamine withdrawal
  • Anticholinergic drug toxicity
  • Neuroleptic malignant syndrome
  • ICU delirium
  • Liver failure
  • Sepsis, CNS infection, or hemorrhage
  • Mania, psychosis
  • Thyroid crisis (3)[C]
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Blood alcohol level, urine drug screen
  • CBC; comprehensive metabolic panel
  • CNS imaging if acute mental status changes
image TREATMENT
The goal is to prevent and treat withdrawal symptoms (e.g., seizures, DTs, cardiovascular events). This is done primarily with BZDs, which reduce the duration of symptoms and raise the seizure threshold.
  • Exclude other medical and psychiatric causes.
  • Provide a quiet, protective environment.
  • The Clinical Institute Withdrawal Assessment for Alcohol Scale revised (CIWA-Ar) is useful for determining medication dosing and frequency of evaluation for AWS. Severity of symptoms are rated on a scale from 0 to 7, with 0 being without symptoms and 7 being the maximum score (except orientation and clouding of sensorium, scale 0 to 4)
    • Nausea and vomiting
    • Tremor
    • Paroxysmal sweats
    • Anxiety
    • Agitation
    • Tactile disturbances
    • Auditory disturbances
    • P.35

    • Visual disturbances
    • Headache or fullness in head
    • Orientation and clouding of sensorium
  • The maximum CIWA-Ar score achievable is 67.
    • Scores >8 are associated with mild withdrawal that will likely resolve without medication.
    • Scores between 8 and 15 are associated with moderate withdrawal which often require management with medication.
    • Scores > 15 are considered severe withdrawal and are associated with the highest risk of seizures and development of DTs.
  • Frequent reevaluation with CIWA-Ar score is crucial.
MEDICATION
First Line
  • BZD monotherapy remains the treatment of choice (4)[A]; it is associated with fewer complications compared with neuroleptics (5)[A].
  • BZD should be chosen by the following considerations:
    • Agents with rapid onset control agitation more quickly (e.g., IV diazepam [Valium]).
    • Long-acting BZDs (diazepam, chlordiazepoxide [Librium]) are more effective at preventing breakthrough seizures and delirium management.
    • Short-acting BZDs (lorazepam [Ativan], oxazepam [Serax]) are preferable when prolonged sedation is a concern (e.g., elderly patients or other serious concomitant medical illness) and preferable when severe hepatic insufficiency may impair metabolism (5)[A].
  • BZD dosages will vary by patients. Given as symptom-triggered or fixed-schedule regimens. Symptom-triggered regimens have been found to require less BZD amounts and reduce hospitalization time (3)[A].
  • Symptom-triggered regimen: Start with chlordiazepoxide 50 to 100 mg PO, repeat CIWA-Ar hourly and if score is ≥8, give additional dose of chlordiazepoxide 50 mg PO. Continue to reevaluate with CIWA-Ar hourly until adequate sedation achieved (score chlordiazepoxide with respective doses of diazepam, lorazepam, or oxazepam) (3)[C].
Second Line
  • Thiamine: 100 mg daily IV or IM for at least 3 days (5)[C]
    • Note that IV glucose administered before treatment with thiamine may precipitate Wernicke encephalopathy and Korsakoff psychosis.
  • β-Blockers (e.g., atenolol [Tenormin]) and α2-agonists (e.g., clonidine [Catapres]) help to control hypertension and tachycardia and can be used with BZDs (3)[C]. Not used as monotherapy due to their inability to prevent DTs and seizures. May worsen underlying delirium
  • Carbamazepine: not recommended as first-line therapy; associated with reduced incidence of seizures but more studies are needed
  • If the patient exhibits significant agitation and alcoholic hallucinosis, an antipsychotic (4,6)[C] (haloperidol [Haldol]) can be used, but this requires close observation, as it lowers the seizure threshold (3)[C].
  • Neuroleptic agents are not recommended as monotherapy due to their association with increased mortality, longer duration of delirium, and complications when compared with sedative agents (7)[A].
ADDITIONAL THERAPIES
Peripheral neuropathy and cerebellar dysfunction merit physical therapy evaluation.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • CIWA-Ar score >15, or severe withdrawal
  • Concurrent acute illness requiring in patient care
  • Poor ability to follow up or no reliable social support
  • Pregnancy
  • Seizure disorder or history of severe alcohol-related seizures
  • Suicide risk
  • Concurrent BZD dependence
  • Age >40 years old
  • Prolonged heavy drinking >8 years
  • Consumes > 1 pint of alcohol or 12 beers per day
  • Random blood alcohol level > 200 mg/dL
  • Elevated MCV, BUN
  • Cirrhosis, liver failure
Discharge Criteria
CIWA-Ar scores of <10 on three consecutive determinations
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Discharge arrangements include transfer to a treatment facility (e.g., sober house or residential program), outpatient substance abuse counseling, peer support groups (Alcoholics Anonymous), and the use of adjuvant treatment such as disulfiram (Antabuse), acamprosate (Campral), or naltrexone (ReVia, Vivitrol).
  • Disulfiram: irreversibly inhibits aldehyde dehydrogenase, blocking alcohol metabolism, leading to an accumulation of acetaldehyde; therefore, it reinforces the individual's desires to stop drinking by providing a disincentive associated with increased acetaldehyde.
    • 250 to 500 mg/day PO for 1 to 2 weeks; maintenance 250 mg/day PO
    • Contraindications: concomitant use of metronidazole and ethanol-containing products, psychosis, severe myocardial disease, and coronary occlusion
  • Acamprosate (666 mg PO TID): Glutamate and GABA modulator indicated to reduce cravings
    • Contraindications: renal impairment (CrCl <30 mL/min)
  • Naltrexone (50 mg/day PO; 380 mg IM every 4 weeks): opiate receptor antagonist, theorized to attenuate pleasurable effects of alcohol and reduce craving. Initiate therapy after patient is opioid-free for at least 7 days.
    • Contraindications: acute hepatitis/liver failure, concomitant opioid therapy
Patient Monitoring
Frequent follow-up to monitor for relapse
PATIENT EDUCATION
  • Alcoholics Anonymous: http://www.aa.org/
  • SMART Recovery (Self-Management and Recovery Training): http://www.smartrecovery.org/ (not spiritually based)
  • National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/guide/
  • FamilyDoctor.Org: alcoholism (Spanish resources available)
PROGNOSIS
Mortality from severe withdrawal (DTs) is 1-5%.
REFERENCES
1. Moyer VA; U.S. Preventive Services Task Force. Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(3):210-218.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
3. Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on pharmacological management of alcohol withdrawal. JAMA. 1997;278(2): 144-151.
4. Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005063.
5. Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537.
6. Minozzi S, Amato L, Vecchi S, et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064.
7. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med. 2004;164(13):1405-1412.
Additional Reading
Sarff M, Gold JA. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med. 2010;38(9)(Suppl): S494-S501.
See Also
Substance Use Disorders
Codes
ICD10
  • F10.239 Alcohol dependence with withdrawal, unspecified
  • F10.230 Alcohol dependence with withdrawal, uncomplicated
  • F10.231 Alcohol dependence with withdrawal delirium
Clinical Pearls
  • The kindling phenomenon has postulated that longterm exposure to alcohol affects neurons, resulting in increased alcohol craving and progressively worse withdrawal episodes (also known as allostasis).
  • Any BZD dose should be patient-specific, sufficient to achieve and maintain a “light somnolence” (e.g., sleeping but easily arousable) and should be tapered off carefully even after AWS resolves to prevent BZD withdrawal.
  • Administer thiamine before patient receives glucose, so as not to precipitate Wernicke encephalopathy.
  • There should be frequent outpatient follow-up to monitor for relapse.
  • Counsel patients taking disulfiram to avoid over-the-counter products that contain alcohol (i.e., mouthwashes).
  • Avoid administering diazepam and lorazepam intramuscularly because of erratic absorption.