P&T News: January/February 2001

Treatment of Alcohol Withdrawal

James J. Amos, M.D., Consult-Liaison Psychiatry
Raymond Crowe, M.D., Director General Hospital Psychiatry
Caroline Carney Doebbeling, M.D., M.S., Medicine-Psychiatry
Jill Liesveld, M.D., Chemical Dependency Center UIHC Psychiatry
Peer Review Status: Internally Peer Reviewed: Adapted from the Recommendations of the Advisory Committee on Immunization Practices

Screening for alcohol dependence can be carried out using the CAGE questionnaire. The CAGE questionnaire is a brief assessment with excellent sensitivity. The clinician should suspect alcoholism if she or he elicits three or more positive answers to the following:

1. Have you often tried to Cut down on your drinking?
2. Have you often been Annoyed by others complaining about your drinking?
3. Have you often felt Guilty about your drinking?
4. Have you often taken a morning drink as an Eye-opener?

Patients who respond positively to three or more questions should be considered at high risk for alcohol dependence and undergo a thorough medical and psychological diagnostic evaluation.

Alcohol dependence is frequently marked by alcohol withdrawal when alcohol intake is stopped or reduced. The following sections will focus on minor withdrawal, major withdrawal (delirium tremens, DT's), withdrawal seizures, and the treatment issues for each.

Alcohol Withdrawal
Signs of alcohol withdrawal occur in 13 to 71% of those presenting for detoxification. About 15% of those hospitalized for detoxification develop withdrawal seizures. The prevalence estimates for delirium tremens vary with the population studied - 0.6% in non-medical detoxification centers, and perhaps 5% overall in those undergoing withdrawal.²

The proposed mechanism of alcohol withdrawal involves the adaptation of the central nervous system to repeated exposure of alcohol on inhibitory GABA A-type neuro-receptors and excitatory NMDA receptors. Animal studies reveal that chronic ethanol administration results in reduced GABA-mediated chloride flux through GABA A-type receptors, indicating tolerance. Chronic ethanol exposure also leads to upregulated NMDA receptor complexes, possibly resulting in the neuronal hyperexcitability that can present clinically as alcohol withdrawal seizures, anxiety, and sleep disturbance.^{3, 4}

The alcohol withdrawal syndrome can be defined as either minor or major. Minor withdrawal criteria are met if the patient has at least three of the following:

1. temperature >38.3º C
2. systolic blood pressure>160
3. diastolic blood pressure>110
4. pulse>110
5. nausea and vomiting
6. tremulousness
7. diaphoresis

Some of the objective signs of withdrawal can be masked by even low doses of beta-adrenergic antagonists, such as propranolol. Criteria 1-4 and 6 could all be below diagnostic threshold if a patient has been taking a beta-adrenergic antagonist, leading to delirium tremens as the first sign of withdrawal. Certain populations, such as those treated with propranolol for portal hypertension, are at higher risk for masked withdrawal and may present to medical care with delirium tremens.

Uncomplicated minor alcohol withdrawal may begin within 12 to 18 hours after the cessation of drinking or simply the reduction of usual intake. It tends to peak between 24 to 48 hours, and usually subsides in 5 to 7 days. Major alcohol withdrawal or delirium tremens typically begins within 48 to 72 hours of the last drink, with peaking of symptoms on days 4 and 5. Major withdrawal may persist from 3 days to several weeks.

Major Withdrawal
Major withdrawal or delirium tremens (DT's) is marked by all the signs and symptoms of minor withdrawal plus delirium. Delirium tremens classically begins about three to five days after stopping or decreasing alcohol intake. However, the DT's may occur up to two weeks after the last drink. There is marked autonomic hyperactivity with elevation of the pulse and blood pressure. Confusion, perceptual disturbances with visual and auditory hallucinations, and marked agitation are prominent features. Often there are associated medical problems such as pneumonia, pancreatitis, subdural hematoma, or myocardial infarction. Patients are often dehydrated and may have multiple fluid and electrolyte imbalances. The mortality rate was as high as 40% in the early part of the 20th century. Improvements in recognition and treatment have led to a decrease in the mortality to approximately 5%.⁵

Alcoholic patients presenting with delirium should be monitored closely for delirium tremens. Importantly, other causes of delirium should be considered given that medical co-morbidity may be present. Stoudemire suggests the medical workup for delirium include a thorough medical history and complete physical examination. The following laboratory tests should be performed:⁶  

Complete blood count with white cell differential Serum electrolytes Liver function tests Blood urea nitrogen Creatinine Fasting blood sugar Electrocardiogram Calcium Magnesium Albumin B12 and folic acid levels Stool guaiac Urinalysis including toxicology screen

Management of Alcohol Withdrawal
Benzodiazepines are the treatment of choice in the pharmacologic management of alcohol withdrawal.^{7, 8, 9} Chlordiazepoxide (Librium®) and lorazepam (Ativan®) are most frequently used because their long half-lives provide for a smoother taper. In general, lorazepam is preferred over longer acting agents such as chlordiazepoxide for patients with liver disease and in the elderly.^{9, 10} For patients who meet criteria for withdrawal, one of these protocols may be followed:  

Chlordiazepoxide Protocol	-or-	Lorazepam Protocol
1. Chlordiazepoxide 50 mg q4 hr x6 doses, then 2. Chlordiazepoxide 50 mg q6 hr x4 doses, then 3. Chlordiazepoxide 25 mg q4 hr x6 doses, then 4. Chlordiazepoxide 25 mg q6 hr x4 doses		1. Lorazepam 2 mg q4 hr x6 doses, then 2. Lorazepam 2 mg q6 hr x4 doses, then 3. Lorazepam 1 mg q4 hr x6 doses, then 4. Lorazepam 1 mg q6 hr x4 doses

The drug is discontinued after the last dose. Lorazepam can be substituted for chlordiazepoxide at a ratio of 1 mg of lorazepam to 25 mg of chlordiazepoxide. Chlordiazepoxide is given orally. Lorazepam can be given either orally or intravenously. Doses should be withheld for nystagmus, sedation, ataxia, or dysarthria. Because the patient is often nutritionally depleted, thiamine 100 mg either intramuscularly or intravenously, folic acid 1 mg, and a multivitamin should be given daily. Thiamine should be given to every patient suspected of alcoholism prior to the administration of dextrose or food to prevent the development of Wernicke's encephalopathy.^{11, 12}

Management of Delirium Tremens
The withdrawal protocol may prevent the development of delirium tremens. For patients in delirium tremens, a suggested regimen is to give 2 mg intravenous lorazepam, increasing the dose until the patient is calm but not obtunded. Adjunctive oral or intravenous haloperidol can be used for agitation and psychosis when benzodiazepines alone are not effective. However, antipsychotics alone are not effective in the management of delirium tremens. One can combine 5 mg haloperidol and 2 to 4 mg lorazepam and administer this every 2 hours until agitation is controlled. Flexibility in dosing is extremely important as simple tapering of the medication according to a schedule may leave the patient inadequately covered for major withdrawal. Clinicians should follow vital signs and the clinical examination. The patient may be comfortable when mild sedation is maintained throughout the course of delirium. The taper should be continued from the dose at which mild sedation is obtained.

Other medications that have been used to treat withdrawal include ethanol, barbiturates, carbamazepine, propofol, beta-blockers, and centrally acting alpha2-agonists such as clonidine.¹³ None have been as well studied as the benzodiazepines. They may mask the hemodynamic signs of withdrawal, or even cause delirium themselves.^{14, 15} Attempting to use ethanol is especially problematic since intravenous administration requires close monitoring of blood concentrations because of toxicity at higher doses. Administering ethanol in the form of beverage alcohol often causes more problems than it solves because of drug interaction issues and unpredictable absorption. In addition, there are the wide variability in tolerance; well-known hepatic, gastrointestinal, hematologic, and neurologic toxicities; and exacerbation of delirious states.⁸ Moreover, since the effectiveness of ethanol has never been proven, its use has been discouraged.¹⁶

Management of Alcohol-Withdrawal Seizures
Alcohol-withdrawal seizures occur about 6 to 48 hours after stopping alcohol. One-third of those having a seizure go on to develop delirium tremens.¹⁴ The seizures usually occur as 1 to 6 generalized tonic-clonic convulsions, which are self-limited.¹⁷ In some series, 10% of patients with chronic alcoholism have recurrent seizures. Other seizure patterns should raise the suspicion of alternative etiologies, such as intra-cranial masses, meningitis, and epilepsy. In most cases of alcohol withdrawal seizures, adding anticonvulsants to benzodiazepines is unnecessary, unless the patient develops status epilepticus. Lorazepam, administered intravenously, usually aborts status epilepticus.¹⁸ Phenytoin (Dilantin®) loading may be done if necessary, but this should be administered with cardiac monitoring. In general, it is unnecessary to prescribe prophylactic anticonvulsants for alcohol withdrawal seizures.

Summary
These are general guidelines for the management of most cases of alcohol withdrawal. The UIHC Consultation-Liaison Psychiatry Service and the Chemical Dependency Center are available for assistance. The Consultation-Liaison Psychiatry Service first call pager is 3080. The Chemical Dependency Center can be reached at extension 4-9364.

References

1. Med Clin North Am 1997; 81(4):881-907.

2. National Institute on Alcohol Abuse and Alcoholism: The Physicians' Guide to Helping Patients with Alcohol Problems. National Institute of Health, 1995, 1-121.

3. Tabakoff B, Hoffman PL. "Neurobiology of alcohol," in Textbook of Substance Abuse Treatment, ed. Galanter M, Kleber HD. Washington, DC. The American Psychiatric Press, 1999: 3-9.

4. Alcohol Alcohol 1998; 33(6):565-75.

5. South Med J 1998; 91(5):425-32.

6. Stoudemire A, Fogel BS, Greenberg SB, eds. Psychiatric Care of the Medical Patient. New York. Oxford UP, 2000.

7. Alcohol Clin Exp Res 1996;20(5):859-76.

8. JAMA 1997; 278(2):144-51.

9. CNS Spectrums 2000;5(2):22-32.

10. Pharmacotherapy 1996;16(1):49-57.

11. Alcohol Alcohol 1998;33(4):317-36.

12. Can Fam Physician 1996;42:2186-90.

13. Crit Care Med 2000;28(6):1781-4.

14. Alcohol Alcohol 1998;33(2):103-15.

15. Masui 1998;47(5):589-92.

16. Ned Tijdsch Geneeskd 2000;144(15):710-3.

17. Can Fam Physician 1996;42:2423-31.

18. N Engl J Med 1998; 339(12):792-8.

DRUGS ADDED TO STOCK

CICLOPIROX

Topical Nail Lacquer: 8%

Ciclopirox (Penlac® - Dermik) topical nail lacquer is indicated for the treatment of mild-to-moderate onychomycosis of fingernails and toenails. Treatment also requires periodic removal of unattached, infected nails by a healthcare professional.

ESTRADIOL CYPIONATE AND MEDROXYPROGESTERONE ACETATE

Injection: 5 mg and 25 mg per 0.5 ml

This combination product (Lunelle® - Pharmacia & Upjohn), which is indicated for the prevention of pregnancy, is injected monthly.

FENOLDOPAM

Injection: 10 mg ampule

Fenoldopam (Corlopam® - Abbott) injection is indicated for the short-term (<48 hours) management of severe hypertension when rapid, reversible, emergency reduction of blood pressure is needed, including malignant hypertension with deteriorating end-organ function.

Note: The use of fenoldopam is restricted to the ICU setting.

TRAMADOL

Tablets: 50mg

Tramadol (Ultram® - Ortho McNeil) tablets are indicated for the management of moderate to moderately severe pain.

Warning: There is an increased risk of seizures with tramadol use if the dose exceeds the recommended dose or if co-administered with selective serotonin reuptake inhibitor antidepressants, tricyclic antidepressants, opioids, monoamine oxidase inhibitors, neuroleptics, other tricyclic compounds (e.g., cyclobenzaprine, promethazine), or other drugs that lower the seizure threshold.

ZINC ACETATE

Capsules: 25 mg , 50 mg

Zinc acetate (Galzin® - Gate/Teva) capsules are indicated for maintenance treatment of patients with Wilson's disease who have initially been treated with a chelating agent.

ADDITIONAL ACTIONS

ASPIRIN 81 mg ENTERIC-COATED TABLETS

An 81 mg enteric-coated tablet was added to stock.

ABACAVIR 300 mg AND LAMIVUDINE 150 mg AND ZIDOVUDINE 300 mg TABLETS

This combination product (Trizivir® - Glaxo Wellcome) was added to stock.

BOTULINUM TOXIN TYPE B INJECTION

This product (Myobloc® - Elan) has been added to stock.

BROMPHENIRAMINE 12 mg AND PSEUDOEPHEDRINE 120 mg SUSTAINED-RELEASE CAPSULES

This product replaced Dimetapp®, which was withdrawn from the market because it contained phenylpropanolamine.

________________________________

DRUGS DELETED FROM STOCK

INDOMETHACIN SUPPOSITORIES

Discontinued by the manufacturer. Indomethacin capsules are available.

PENTOBARBITAL 60 mg SUPPOSITORIES

Discontinued by all manufactures. Pentobarbital injection is available.

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