Withdrawal symptoms usually, but not always, occur in stages: tremulousness or jitteriness (6-8 hours), psychosis and perceptual symptoms (8-12 hours), seizures (12-24 hours), and delirium tremens ([DTs], 24-72 hours, up to 1 week).

Notably, alcohol withdrawal, particularly DTs, can be fatal.]

 

Differential Diagnosis

Included in the differential diagnosis for alcohol withdrawal are other drug withdrawal states, especially sedative-hypnotic withdrawal. In fact, the criteria for withdrawal from substances such as benzodiazepines (most commonly short-acting, high-potency drugs) and barbiturates are identical to those for alcohol withdrawal. A carefully recorded history, a physical examination, and laboratory results indicative of long-term, heavy alcohol use (eg, evidence of cirrhosis or liver failure, macrocytic anemia, elevated liver transaminase levels-particularly gamma-glutamyl transpeptidase) will point to the correct diagnosis.

Medical conditions with similar signs and symptoms must be ruled out. Examples of such conditions include thyroid storm (thyrotoxicosis), pheochromocytoma, and inappropriate use of beta-agonist inhalers or sympathomimetics.

Although hallucinations are rare in alcohol withdrawal without delirium, if present they can be confused with those of schizophrenia. Several features distinguish the two conditions: In alcohol withdrawal, the perceptual disturbances are transient, there is not necessarily a history of a preexisting psychotic illness, the associated symptoms of schizophrenia are not present, and the patient's reality testing ability remains intact.

 

Case Correlation

Hypoglycemia and diabetic ketoacidosis may also cause symptoms similar to alcohol withdrawal.
  • DIAPHORESIS: Excessive sweating.

  • SYMPATHOMIMETIC: A substance that mimics at least some adrenalin or catecholamine responses. Examples of sympathomimetic substances include caffeine, ephedrine, and amphetamines.

Clinical Approach

 

 

 

[Positron emission tomographic (PET) studies have suggested a globally low rate of metabolic activity, particularly in the left parietal and right frontal areas in otherwise healthy persons withdrawing from alcohol.

 

  • [CIWA-Ar is recommended for determining the need to treat alcohol withdrawal.]

 

 

 

The most common treatment for alcohol withdrawal remains benzodiazepines, administered either orally or parenterally.

 

If liver function is not impaired, a long-acting benzodiazepine such as chlordiazepoxide or diazepam is generally preferable given PO or IV.

In general benzodiazepines depress the central nervous system and cause drowsiness and sleepiness.

Although the exact mechanism by which each Benzodiazepine works is not fully understood, it involves enhancing the effects of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. This slows down nerve impulses throughout the entire body and drastically reduces the brain’s output of other neurotransmitters such as Norepinephrine, Serotonin, acetyl choline and dopamine. These neurotransmitters are necessary for alertness, memory, muscle tone and coordination, emotional responses, endocrine gland secretions, heart rate, and blood pressure. The use of benzos impairs all of these functions which results in a relaxed state.

If there is concern about decreased liver function, lorazepam can be administered either orally or parenterally, as its metabolism is not as dependent on liver function, and, as such, is probably the most popular agent utilized. Similarly, oxazepam may be preferred in these instances. Whatever the specific drug used, it should be given as frequently as necessary in order to normalize the vital signs and sedate the patient. The medicine should then be gradually tapered over the next several days, and the patient's vital signs monitored. Use of the Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar) may be useful in standardizing the assessment of withdrawal severity and assist in guiding treatment. Anticonvulsants such as carbamazepine and valproic acid are also effective in treating alcohol withdrawal, although it is a much less popular option in the United States given familiarity with treatment with benzodiazepines. Antipsychotics should be avoided, because of their potential to lower the seizure threshold.

 

 

 

  • Many of alcohol withdrawal symptoms seen are due to increased CNS activity, particularly agitation and autonomic hyperactivity such as an increase in heart rate, respiratory rate, and temperature.
  • DTs refers to delirium associated with a tremor and autonomic hyperactivity, and generally occurs 2 to 7 days after stopping the use of alcohol.
  • Benzodiazepines are the preferred class of drugs to treat the alcohol withdrawal syndrome.

 

 

Therefore, under the suspicion of alcohol withdrawal, it is necessary to calculate Clinical Institute Withdrawal Assessment for Alcohol scale (revised) (CIWA-Ar; see below) score to determine the use of benzodiazepine.

Currently, CIWA-Ar is recommended for determining the need to treat alcohol withdrawal. In general, a score of less than 10 requires no pharmacologic treatment; a score of 10 to 20 requires at least later assessment, if not treatment; and a score of more than 20 usually merits pharmacologic treatment or a gradual increase to a higher dosage for a person receiving treatment.

Clinical Institute Withdrawal Assessment for Alcohol Scale

Scoring

The cumulative score provides the basis for treatment of patients undergoing alcohol withdrawal (Table 9-1).


Table 9-1. CIWA Scoring Interpretation

Cumulative Score
0–8 No medication is necessary
9–14 Medication is optional for patients with a score of 8–14
15–20 A score of ≥15 requires treatment with medication
>20 A score of >20 poses a strong risk of delirium tremens
67 Maximum possible cumulative score

 

If the score is more than 20, pharmacologic treatment is indicated. Since dose of benzodiazepine needs to be adjusted according to patient's symptom report, you should make sure that the patient is able to communicate his symptoms before implementing the protocol.

The easiest method to screen a patient at risk of alcohol withdrawal is the CAGE mnemonic (cut–annoyed–guilty–eye opener). More than 2 positive responses correlate highly with severe alcohol abuse and should raise concerns as to whether the patient will experience alcohol withdrawal.

Diagnosis

Currently, CIWA-Ar is recommended for determining the need to treat alcohol withdrawal. In general, a score of less than 10 requires no pharmacologic treatment; a score of 10 to 20 requires at least later assessment, if not treatment; and a score of more than 20 usually merits pharmacologic treatment or a gradual increase to a higher dosage for a person receiving treatment.

Clinical Institute Withdrawal Assessment for Alcohol Scale

Scoring

The cumulative score provides the basis for treatment of patients undergoing alcohol withdrawal (Table 9-1).

Table 9-1. CIWA Scoring Interpretation
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Assessment Tool

Nausea and Vomiting

Ask: “Do you feel sick to your stomach? Have you vomited?” (See Table 9-2.)

Table 9-2. Nausea Scoring
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Tremor

Arms extended and fingers spread apart (Table 9-3).

Table 9-3. Tremor Scoring
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Paroxysmal Sweats

See Table 9-4.

Table 9-4. Sweating Scoring
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Anxiety

Ask: “Do you feel nervous?” (See Table 9-5.)

Table 9-5. Anxiety Scoring
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Agitation

See Table 9-6.

Table 9-6. Activity Scoring
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Tactile Disturbances

Ask: “Have you any itching, pins and needles sensations, burning sensations, or numbness, or do you feel bugs crawling on or under your skin?” (See Table 9-7.)

Table 9-7. Neurologic Scoring
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Auditory Disturbances

Ask: “Are you more aware of sounds around you? Are they harsh? Do they frighten you? Are you hearing anything that is disturbing to you? Are you hearing things you know are not there?” (See Table 9-8.)

Table 9-8. Auditory Disturbance Scoring
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Visual Disturbances

Ask: “Does the light appear to be too bright? Is its color different? Does it hurt your eyes? Are you seeing anything that is disturbing to you? Are you seeing things you know are not there?” (See Table 9-9.)

Table 9-9. Visual Disturbance Scoring
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Headache, Fullness in Head

Ask: “Does your head feel different? Does it feel as if there is a band around your head?” Do not rate for dizziness or light-headedness. Otherwise, rate severity (Table 9-10).

Table 9-10. Headache Scoring
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Orientation and Clouding of Sensorium

Ask: “What day is this? Where are you? Who am I?” (See Table 9-11.)

Table 9-11. Orientation Scoring
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Besides patient's history on alcohol, what clues may help us figure out to define possible alcohol use and risk of developing withdrawal symptoms?

Physical examinations may give you clues about alcohol abuse: mild fluctuation hypertension, repeated infections such as pneumonia, particularly aspiration pneumonia, and otherwise unexplained cardiac arrhythmias such as atrial fibrillation (so-called “holiday heart syndrome”).

If a patient has severe alcoholism enough to produce liver damage, changes in liver function tests such as an AST:ALT ratio >2:1 may be seen. Among other laboratory tests, elevated carbohydrate-free transferrin (>20 U/L) and gamma-GT (>35 U) are the most sensitive and specific (>70%) to make a diagnosis of alcohol abuse; the combination of the 2 is likely to be more accurate than either alone. These tests are also useful in monitoring abstinence as well. Other than the aforementioned tests, a high MCV (>91 μm3) and serum uric acid (>7 mg/dL) can be useful in identifying heavy drinkers.

Once alcoholism is confirmed through either history or laboratory tests, we should start some interventions to prevent alcohol withdrawal syndromes.

The primary effect of alcohol on the CNS is depression of excitability and conduction, so patients with alcoholism seem to have compensated for the depressant effect because the brain has been exposed repeatedly to high doses of alcohol. When alcohol intake is terminated or the alcohol level in the CNS decreases, withdrawal symptoms occur. Since withdrawal is a form of rebound overactivations from the suppression, many of these withdrawal symptoms are the opposite of those produced by intoxication. That is, symptoms of increased CNS activity, particularly agitation, and autonomic hyperactivity such as an increase in heart rate, respiratory rate, and temperature are seen. Patients may develop various withdrawal signs and symptoms depending on the time from the last alcohol use.

Alcohol psychosis develops 12 to 24 hours after discontinuing alcohol use. Patients typically have distinctive visual hallucination without autonomic instability. This is in contrast to the tactile hallucination with autonomic instability in DTs.

Alcohol withdrawal seizures (typically a single generalized seizure) may occur within 48 hours after stopping alcohol, and usually do not require prophylactic antiseizure medications.

DTs refers to delirium associated with a tremor and autonomic hyperactivity, and generally occurs 2 to 7 days after stopping alcohol. This is seen in <5% of alcohol-dependent individuals. The chance of DTs during any single withdrawal is <1%. DTs is most likely to develop in patients with concomitant severe medical disorders. However, in case of very severe alcoholism, patients may have DTs earlier than the typical time frame. In this case, they may have positive blood alcohol in spite of the presence of DTs, which means that their brains have been chronically and severely depressed by higher alcohol. Consequently, their hospital courses and detoxifications may take much longer and be more likely complicated.

Treatment

The goals of treatment are amelioration of symptoms and prevention of complications.

Mild symptoms can be managed supportively. If a patient progresses symptomatically despite supportive measures, pharmacologic treatment should be instituted. Most withdrawal symptoms are caused by the rapid removal of a CNS depressant (in this case, alcohol). The symptoms can be controlled by administering any CNS depressant in doses that decrease agitation, and gradually tapering the dose over 3 to 5 days.

High-dose benzodiazepine is a drug of choice if pharmacologic treatment is required.

Among CNS depressants, benzodiazepines have the highest margin of safety and lowest cost and are, therefore, the preferred class of drugs. All benzodiazepines are effective in the treatment of alcohol withdrawal symptoms. Benzodiazepines with a short half-life are especially useful for patients with serious liver impairment or preexisting encephalopathy. However, short-acting benzodiazepines such as lorazepam can produce rapidly changing drug blood levels and must be given every 4 hours to avoid abrupt fluctuations that may increase the risk of seizures. Therefore, most clinicians use drugs with longer half-lives, such as diazepam or chlordiazepoxide.

Dosage can be adjusted by a symptom.

A key point in treating alcohol withdrawal is to begin with a larger dose of benzodiazepines than usual, which are prescribed for anxiety. The patient's response should be observed, and the dosage needs to be adjusted accordingly. Previously, fixed-dose schedules were used for the treatment, but multiple studies have shown that a symptom-triggered approach may be as efficacious as the fixed one and result in less drug use.

Prerequisite to start CIWA-Ar protocol.

Before implementing a symptom-triggered protocol, 2 factors should be considered: first, is the patient at risk of developing alcohol withdrawal syndrome? (A remote history of alcoholism does not increase the risk of symptom development and therefore doesn't need a treatment protocol.) Second, does the patient have intact verbal communication? Since this protocol is a symptom-triggered treatment, it is ineffective if the patient is not able to communicate symptoms.

In addition to alcohol withdrawal syndrome, there are other medical problems complicating the treatment of patients with alcohol withdrawal, especially nutritional deficiencies:

  1. Thiamine deficiency:

      1. Wet beriberi (aka beriberi syndrome) is characterized by high output heart failure (alcoholism is 1 of the reversible causes of dilated cardiomyopathy).

      1. Dry beriberi (either Wernicke syndrome or Korsakoff psychosis).

    In Wernicke syndrome, patients typically manifest ataxia, ophthalmoplegia (diplopia with nystagmus due to lateral gaze palsy, often affecting VI cranial nerve, abducens nerve), and confusion.

    In Korsakoff psychosis, patients may develop a combination of anterograde and retrograde amnesia, confabulation, or spur cell on peripheral blood smear. It is associated with a poor prognosis.

    Management: give thiamine first before replacing glucose in patients with alcoholism. Thiamine is a vital cofactor for glucose metabolism; therefore, giving glucose prior to thiamine would worsen the status of the patient.

  2. Refeeding syndrome (phosphate deficiency): Patients who chronically use alcohol are phosphate-depleted as well. If they are fed a high-carbohydrate diet without correcting hypophosphatemia, it will lead to the depletion of more phosphate because it will be used to make ATP and phosphate-bound glucose in the liver and muscles. Consequently, patients may develop hemolysis, muscle breakdown, and respiratory distress.

  3. Vitamin B12 and folate deficiency: Clinically, vitamin B12 results in both hematologic and neurologic sequelae while folate deficiency causes only hematologic problems.

    Biochemically, the level of vitamin B12 and folate can be measured directly. However, the folate level can be affected by even 1 folate-rich diet, making it appear normal. Moreover, vitamin B12 levels are often borderline low (250–500). If these levels are normal but clinical suspicion is high, measure the indirect metabolites of vitamin B12 and folate: MMA and homocysteine. If both are elevated, there is a vitamin B12 deficiency, and if only homocysteine is high, a folate deficiency is likely present.

    In vitamin B12 deficiency, neurologic complications come first before hematologic manifestations such as megaloblastic anemia (MCV is often higher than 110). Therefore, even without hematologic findings, dementia or gait problem such as a “high stepping gait” in a clinical context may be a symptom of vitamin B12 deficiency.

  4. Miscellaneous: hyponatremia (beer potomania), magnesium deficiency, and calcium deficiency.

 

 

 

Severe alcohol withdrawal with autonomic instability (delirium tremens or DTs) has a high mortality and requires stabilization in an acute medical facility.

Content 13

 

A 48-year-old man is admitted to a hospital because of pneumonia. Two days after the hospitalization, the patient becomes agitated and restless with tachycardia and hypertension. On physical examination, the patient is noted to be alert, but anxious, tremulous, and disoriented to place and time. And these findings differ from those on examination at admission. His alcohol history is significant (eg, drinking 3 or more vodkas a day for years; most recent alcohol intake occurred 2 days before coming to the hospital), but no history of liver diseases or alcohol withdrawal is evident. Subsequent physical examinations reveal no specific changes from the admission assessment except disorientation and anxiety. His respiratory status appears stable, and repeated CXR does not show any progression compared with the admission assessment. Routine laboratory workups including CBC, CMP, EKG, and blood glucose are stable. Since he has a history of alcohol dependence, alcohol withdrawal is considered.

Content 2

Content 3

A 50-year-old salesman was admitted to the hospital with acute appendicitis. He has no significant medical history, takes no medications, does not smoke cigarettes, and has an alcoholic beverage “once in a while with the boys.” He underwent an uncomplicated appendectomy. On the second hospital day, you find him to be quite agitated and sweaty. His temperature, heart rate, and blood pressure are elevated. A short time later he has a grand mal seizure. You suspect that he is having withdrawal symptoms from chronic alcohol abuse and give IV lorazepam for immediate control of the seizures and plan to start him on oral chlordiazepoxide when he is more stable.

Questions

What are the acute pharmacologic effects of ethanol?

What are the chronic pharmacologic effects of ethanol?

How is alcohol metabolized?

What is the pharmacologic basis for using benzodiazepines to manage alcohol withdrawal?

Answers to Case 23: Drugs of Abuse

Summary: A 50-year-old man is displaying symptoms and signs of acute alcohol withdrawal.

  • Symptoms of acute ethanol toxicity: Disinhibited behavior and judgment, slurred speech, impaired motor function, depressed and impaired mental function, respiratory depression, cutaneous vasodilation, diuresis, gastrointestinal side effects, and impaired myocardial contractility.

  • Symptoms of chronic ethanol toxicity: Alcoholic fatty liver, alcoholic hepatitis, cirrhosis, liver failure, peripheral neuropathy, alcohol amnesic syndrome, pancreatitis, gastritis, fetal alcohol syndrome, nutritional deficiencies, cardiomyopathy, cerebellar degeneration.

  • Metabolism of alcohol: Oxidized primarily in the liver but also in the stomach and other organs to acetaldehyde by the cytosolic enzyme alcohol dehydrogenase and by hepatic microsomal enzymes; acetaldehyde is oxidized to acetate by hepatic mitochondrial aldehyde dehydrogenase.

  • Benzodiazepines in alcohol withdrawal: Both alcohol and the benzodiazepines enhance the effect of γ-aminobutyric acid (GABA) on GABAA receptors, resulting in decreased overall brain excitability. This cross-reactivity explains why relatively long-acting benzodiazepines (eg, lorazepam, chlordiazepoxide) can be substituted for alcohol in a detoxification program.

Clinical Correlation

Ethanol is the most widely used CNS depressant. It is rapidly absorbed from the stomach and small intestine and distributed in total body water. Its exact mechanism of action is not known, but may be related to its generally disruptive effects on cell membrane protein functions throughout the body, including effects on signaling pathways in the CNS. At low doses it is oxidized by cytoplasmic alcohol dehydrogenase. At higher doses it is also oxidized by liver microsomal enzymes, which may be induced by chronic use. These enzymes are rapidly saturated by the concentrations of alcohol achieved by even one or two alcoholic drinks so that its rate of metabolism becomes independent of plasma concentration. Tolerance to the intoxicating effects of alcohol can develop with chronic use. Genetic variations in aldehyde dehydrogenase occur such that certain individuals display impaired ability to metabolize alcohol. The acetaldehyde metabolite accumulates in these individuals causing demonstrate a characteristic flushing of the skin upon drinking alcohol and increasing the likelihood of acute alcohol intoxication.

Cross-tolerance with barbiturates and benzodiazepines may also develop. Because of this cross-tolerance effect, benzodiazepines are the most commonly used agents for the treatment of alcohol withdrawal, a potentially life-threatening syndrome commonly seen 2–3 days after the abrupt cessation of alcohol use by a chronic abuser. A long-acting benzodiazepine can be taken, and gradually tapered, to mitigate this effect. Disulfiram is also used on occasion to manage alcoholism. It is a drug that inhibits aldehyde dehydrogenase that in the presence of alcohol causes an accumulation of acetaldehyde, which results in a highly aversive reaction consisting of flushing, severe headache, nausea and vomiting, and confusion. Naltrexone, an opioid antagonist, is yet another drug used to manage alcoholism.