Alcohol Withdrawal Syndrome: From CIWA to Phenobarbital

Proactive Management Prevents ICU Transfers

A Comprehensive Review for Internal Medicine Trainees

Dr Neeraj Manikath , claude.ai

Abstract

Alcohol withdrawal syndrome (AWS) represents one of the most preventable causes of morbidity and mortality in hospitalized patients. Despite its predictability, AWS continues to result in preventable ICU transfers, prolonged hospitalizations, and tragic outcomes when management is delayed or inadequate. This review provides a comprehensive, protocol-driven approach to AWS management, emphasizing prophylaxis, appropriate use of the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scale, advanced strategies including phenobarbital loading for refractory cases, and essential discharge planning. Understanding these principles transforms AWS from a crisis into a manageable condition.

Introduction

Alcohol use disorder affects approximately 14.5 million Americans, and AWS develops in up to 50% of hospitalized patients with chronic heavy alcohol use who abruptly discontinue drinking.[1] The spectrum ranges from minor tremulousness to life-threatening delirium tremens (DT), which carries a mortality rate of 5-15% even with treatment.[2] The tragedy of AWS lies not in its complexity but in its preventability—most severe cases result from delayed recognition or inadequate prophylaxis rather than treatment failure.

The cornerstone of modern AWS management rests on three principles: early identification of at-risk patients, aggressive prophylaxis, and protocol-driven escalation. This review translates these principles into actionable strategies for the busy internist.

Prophylaxis is Key: Identifying and Treating Before Symptoms Emerge

Pearl #1: The best AWS protocol is the one that prevents withdrawal from starting.

Risk Stratification

Every admission requires systematic screening for alcohol use. The CAGE questionnaire (Cut down, Annoyed, Guilty, Eye-opener) or AUDIT-C provides rapid assessment, but the most critical question remains simple: "When was your last drink?" Patients typically develop symptoms 6-24 hours after cessation, with peak severity at 48-72 hours.[3]

High-risk features include:

History of previous withdrawal seizures or DT
Heavy daily use (>8 drinks/day for men, >6 for women)
Concurrent benzodiazepine or barbiturate dependence
Multiple previous detoxifications (the "kindling" phenomenon)[4]
Elevated mean corpuscular volume (MCV >100 fL)
Elevated liver enzymes with AST:ALT ratio >2:1

Hack #1: Check the admission vitals. Tachycardia (HR >100) and hypertension (SBP >140) in the emergency department, even before other symptoms appear, often represent early autonomic hyperactivity from incipient withdrawal.

Scheduled Prophylactic Benzodiazepines

For patients with heavy use patterns, scheduled benzodiazepines prevent rather than treat withdrawal. Chlordiazepoxide (Librium) offers several advantages: long half-life (24-48 hours), active metabolites that provide smooth coverage, and lower abuse potential compared to shorter-acting agents.[5]

Standard prophylactic regimen:

Chlordiazepoxide 50 mg PO every 6 hours for 4 doses
Then 25 mg every 6 hours for 8 doses
Then 25 mg every 12 hours for 4 doses
Then discontinue

This fixed-schedule approach provides 72 hours of protection during the highest-risk period. For patients unable to take oral medications, lorazepam 2 mg IV every 6 hours provides equivalent coverage with a similar taper schedule.[6]

Pearl #2: Don't wait for symptoms to treat. By the time CIWA scores rise, you're already behind. Prophylaxis shifts the paradigm from reactive to proactive care.

The CIWA-Ar Protocol: Proper Use and Inherent Limitations

The CIWA-Ar scale revolutionized AWS management by standardizing assessment and treatment thresholds. However, its utility depends entirely on appropriate patient selection and proper administration.

Understanding CIWA-Ar Components

The 10-item scale assesses:

Nausea/vomiting (0-7)
Tremor (0-7)
Paroxysmal sweats (0-7)
Anxiety (0-7)
Agitation (0-7)
Tactile disturbances (0-7)
Auditory disturbances (0-7)
Visual disturbances (0-7)
Headache (0-7)
Orientation/clouding of sensorium (0-4)

Maximum score: 67 points. Scores <8 indicate minimal withdrawal, 8-15 moderate withdrawal, and >15 severe withdrawal.[7]

Standard CIWA-Ar Protocol

Assessment frequency:

Every 4 hours if score <8
Every 2 hours if score 8-15
Every 1 hour if score >15

Treatment thresholds:

CIWA ≥8: Administer benzodiazepine (typically chlordiazepoxide 50-100 mg or lorazepam 2-4 mg)
Reassess in 1 hour
Repeat dosing if score remains ≥8
No maximum dose—treat to clinical effect[8]

Hack #2: Front-load aggressively in severe withdrawal. If initial CIWA score is >20, give two doses of benzodiazepine immediately (e.g., lorazepam 4 mg followed by another 4 mg 15 minutes later). This rapidly establishes control rather than chasing escalating symptoms.

Critical Limitations of CIWA-Ar

The CIWA-Ar's subjective components make it unreliable in specific populations:

When CIWA fails:

Altered mental status from other causes: Hepatic encephalopathy, concurrent delirium, dementia, or intoxication makes symptom reporting impossible
Intubated/sedated patients: Cannot assess subjective symptoms
Polysubstance use: Concurrent stimulant or opioid withdrawal confounds scoring
Language barriers: Requires clear communication
Elderly patients: May not mount typical hyperadrenergic response; confusion predominates over tremor[9]

Oyster #1: The "quiet" elderly patient with AWS. An 78-year-old patient may appear calm with a CIWA score of 6 but have profound disorientation and be at high seizure risk. In elderly patients, monitor for confusion and autonomic instability rather than relying solely on CIWA scoring. Consider prophylactic benzodiazepines based on history alone.

Objective AWS Assessment (Modified CIWA)

For patients unable to report symptoms, use objective measures:

Heart rate >100 bpm (1 point)
Systolic BP >140 mmHg (1 point)
Temperature >37.5°C (1 point)
Diaphoresis (1 point)
Tremor (1 point)
Agitation (1 point)

Treat if ≥3 objective signs present.[10]

When CIWA Fails: The Phenobarbital Strategy

Despite aggressive benzodiazepine therapy, 5-10% of patients develop refractory withdrawal characterized by escalating benzodiazepine requirements (>40 mg diazepam equivalents in 2 hours), persistent autonomic instability, or progression to DT.[11]

Understanding Phenobarbital's Mechanism

Alcohol and benzodiazepines primarily enhance GABA-A receptor function. Chronic alcohol exposure causes receptor downregulation and compensatory upregulation of excitatory NMDA receptors. Phenobarbital offers advantages beyond benzodiazepines:

Direct GABA-A agonism (benzodiazepines only enhance endogenous GABA)
Longer half-life (80-120 hours) providing sustained coverage
Less respiratory depression at therapeutic doses
NMDA receptor antagonism addressing excitotoxicity
Anticonvulsant properties independent of GABA mechanisms[12]

The Phenobarbital Loading Protocol

Indications:

Benzodiazepine requirements >40 mg lorazepam equivalents in 24 hours
Persistent CIWA scores >15 despite adequate benzodiazepines
History of DT or seizures during current admission
Concurrent medical conditions limiting benzodiazepine use (respiratory compromise, hepatic failure)
Polysubstance withdrawal including sedative-hypnotics[13]

Loading dose calculation:

Standard load: 10-15 mg/kg ideal body weight
For a 70 kg patient: 10 mg/kg = 700 mg total load
Divide into divided doses for safety

Administration protocol:

Give 130-260 mg IV/IM every 20-30 minutes
Maximum rate: 60 mg/minute IV
Target clinical endpoint: mild sedation, nystagmus, or light slurred speech
Continue until patient comfortable or reaches load limit[14]

Hack #3: Phenobarbital front-loading in the ED. For patients presenting with severe AWS (CIWA >20) or history of complicated withdrawal, initiate phenobarbital loading immediately rather than waiting for benzodiazepine failure. One study showed phenobarbital-first protocols reduced ICU admissions by 72%.[15]

Adjunctive Phenobarbital Strategy

For less severe refractory cases, add phenobarbital to existing benzodiazepine therapy:

Phenobarbital 60-120 mg IV/IM every 6-8 hours
Continue CIWA-guided benzodiazepines
Taper benzodiazepines first, then phenobarbital

Safety Considerations

Contraindications:

Porphyria
Severe respiratory depression (use caution, not absolute)
Known phenobarbital allergy

Monitoring:

Continuous pulse oximetry initially
Vital signs every 30 minutes during loading
Monitor for over-sedation (target: arousable to voice)
Serum levels generally unnecessary (treat clinical response)

Pearl #3: Phenobarbital and benzodiazepines are synergistic but safe. The feared respiratory depression rarely occurs at therapeutic doses. The goal is comfort, not obtundation. Trust the protocol.

Critical Adjunctive Management

Thiamine, Folate, and Multivitamins: Not Optional

Wernicke encephalopathy develops in up to 12% of hospitalized patients with alcohol use disorder.[16] The classic triad (confusion, ataxia, ophthalmoplegia) appears in only 16% of cases—absence of classic features does not exclude diagnosis.

Mandatory prophylaxis:

Thiamine 500 mg IV three times daily for 3-5 days before or with any glucose administration
Then thiamine 250 mg IV/PO daily until eating regular diet
Folate 1 mg daily
Multivitamin daily

Oyster #2: The glucose-induced Wernicke's. A 52-year-old malnourished patient receives D5W for hypoglycemia before thiamine. Hours later, profound confusion and ophthalmoplegia develop. IV dextrose depletes remaining thiamine stores, precipitating acute Wernicke encephalopathy. Always give thiamine first.

Correcting Metabolic Derangements

AWS creates a catabolic state with multiple abnormalities:

Hypomagnesemia (present in 30% of patients):

Increases seizure risk
Impairs benzodiazepine efficacy
Replacement: Magnesium sulfate 2 g IV every 6 hours for 4 doses, then daily[17]

Hypokalemia and hypophosphatemia:

Monitor daily
Aggressive repletion to prevent arrhythmias and respiratory muscle weakness

Fluid resuscitation:

Patients are typically dehydrated from poor intake, diaphoresis, and vomiting
Target 2-3 liters in first 24 hours unless contraindicated

Symptom-Specific Adjuncts

Beta-blockers (atenolol 50-100 mg daily):

Controls tachycardia and hypertension
Does NOT reduce seizure risk or DT incidence
Use as adjunct, never monotherapy[18]

Alpha-2 agonists (clonidine 0.1-0.2 mg every 6 hours):

Reduces sympathetic hyperactivity
Useful for persistent hypertension
Again, adjunctive only

Antipsychotics: Generally avoided

Lower seizure threshold (especially haloperidol)
Reserved for severe agitation unresponsive to benzodiazepines
If needed: quetiapine 25-50 mg has lowest seizure risk[19]

Preventing Complications

Seizure Prophylaxis

Withdrawal seizures occur in 5-15% of untreated patients, typically within 12-48 hours of last drink. They are usually generalized tonic-clonic, brief, and self-limited—but herald potential progression to DT.[20]

If seizure occurs:

Ensure adequate benzodiazepine loading
Consider phenobarbital if not already initiated
No role for chronic anticonvulsants (phenytoin, levetiracetam)—these do not prevent AWS seizures
Benzodiazepines are both treatment and prophylaxis

Pearl #4: One seizure demands aggressive escalation. A withdrawal seizure is a red flag that current therapy is inadequate. Immediately reassess dosing strategy.

Aspiration Precautions

Patients with altered mental status require:

NPO status until stable
Aspiration precautions
Consider nasogastric tube for medication administration if needed

Discharge Planning: Completing the Continuum

Successfully treating AWS is meaningless without addressing the underlying disorder. Brief intervention and warm hand-offs to addiction services reduce 30-day readmissions by 40%.[21]

The FRAMES Approach to Brief Intervention

Feedback: "Your liver enzymes are elevated from alcohol"
Responsibility: "Only you can make changes"
Advice: Clear recommendation to reduce/stop
Menu: Offer treatment options
Empathy: Non-judgmental stance
Self-efficacy: Express confidence in ability to change[22]

Pharmacotherapy Options

Naltrexone 50 mg daily:

Reduces cravings and heavy drinking days
Blocks endorphin reward from alcohol
Start before discharge

Acamprosate 666 mg three times daily:

Modulates glutamate transmission
Reduces protracted withdrawal symptoms
Requires good renal function

Disulfiram 250 mg daily:

Aversive therapy (causes severe reaction with alcohol)
Requires patient commitment and monitoring[23]

Warm Hand-Off Essentials

Before discharge:

Schedule outpatient addiction medicine appointment (ideally within 7 days)
Provide local AA/SMART Recovery meeting schedules
Prescribe naltrexone or acamprosate
Bridge benzodiazepine prescription (3-5 days) if needed
Ensure housing stability and support system

Hack #4: In-hospital addiction consultation. If available, addiction medicine consultation during admission increases treatment engagement by 60%. Make the introduction before discharge, not at discharge.[24]

Putting It All Together: A Practical Algorithm

Step 1: Identify risk (every admission)

CAGE/AUDIT-C screening
"When was your last drink?"
Review for high-risk features

Step 2: Initiate prophylaxis (heavy users)

Chlordiazepoxide 50 mg q6h × 4, then taper
Thiamine 500 mg IV TID
Magnesium, folate, multivitamin

Step 3: CIWA-Ar monitoring (if appropriate)

Standard protocol: treat score ≥8
Objective scoring if unable to self-report
Front-load aggressively if score >20

Step 4: Recognize early failure

Escalating doses (>40 mg lorazepam equivalents/24 hrs)
Persistent CIWA >15
One seizure

Step 5: Phenobarbital protocol

Load: 10-15 mg/kg divided doses
Continue benzodiazepines initially
Transition to phenobarbital maintenance

Step 6: Discharge bundle

Brief intervention
Pharmacotherapy prescription
Scheduled addiction medicine follow-up
Support resources

Conclusion

Alcohol withdrawal syndrome epitomizes preventable hospital morbidity. The tools exist—prophylactic benzodiazepines, CIWA-guided therapy, phenobarbital rescue protocols, and nutritional support—yet adverse outcomes persist when these strategies are delayed or incompletely applied. The modern internist must shift from reactive crisis management to proactive risk assessment and aggressive early intervention.

Remember the fundamental principles: identify early, treat prophylactically, escalate appropriately, and connect to ongoing care. Every ICU transfer for refractory withdrawal represents a missed opportunity for earlier, more aggressive therapy. Every hospital discharge without addiction resources represents a missed opportunity for life-changing intervention.

AWS management is not complex—it simply demands vigilance, protocol adherence, and commitment to comprehensive care. Master these principles, and you will prevent suffering, save lives, and potentially alter the trajectory of your patients' futures.

Key Pearls Summary

Prevention beats treatment: Prophylactic benzodiazepines for all high-risk patients
The quiet elderly patient: Low CIWA scores may mask serious withdrawal
Phenobarbital is safe and synergistic: Don't fear combining with benzodiazepines
One seizure demands escalation: Signals inadequate current therapy
Thiamine always before glucose: Prevent iatrogenic Wernicke encephalopathy
Front-load aggressively: Control symptoms early rather than chasing escalation
Discharge planning starts at admission: Addiction medicine consultation saves lives

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Conflicts of Interest: None declared

Funding: None

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