Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Alcohol intoxication and the alcohol withdrawal syndrome Clive C. Robertson BM, BCh & Edward M. Sellers MD, PhD To cite this article: Clive C. Robertson BM, BCh & Edward M. Sellers MD, PhD (1978) Alcohol intoxication and the alcohol withdrawal syndrome, Postgraduate Medicine, 64:6, 133-138, DOI: 10.1080/00325481.1978.11715005 To link to this article: http://dx.doi.org/10.1080/00325481.1978.11715005
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Newcastle, Australia]
Date: 26 December 2016, At: 12:39
Sixth of seven symposium articles in this issue
Alcohol intoxication and the alcohol withdrawal syndrome Consider How does the hepatic metabolism rate of ethanol in chronic alcohol abusers compare with that in nonabusers? What are the biochemical physiologic abnormalities that may produce metabolic encephalopathy in alcoholic patients? What signs and symptoms characterize the alcohol withdrawal syndrome?
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
Clive C. Robertson, BM, BCh Edward M. Sellers, MD, PhD
Although acute alcohol intoxication can cause death, hepatic metabolism of ethanol is usually rapid, and in most cases general supportive care of the intoxicated patient is all that is required. Abrupt cessation of prolonged excessive alcohol intake gives rise to the alcohol withdrawal syndrome. The fundamentals of treatment are careful assessment of the patient and judicious use of a benzodiazepine. Alcohol intoxication and in particular the alcohol withdrawal syndrome constitute two important medical components of the major public health problem of alcoholism. The long-term treatment of alcohol abuse largely involves sociobehavioral approaches. This discussion is restricted to consideration of intoxication and the consequences of abrupt cessation of alcohol intake, both of which may produce significant morbidity and even mortality. Alcohol intoxication Clinical features- The clinical picture of acute alcohol intoxication is influenced by various factors, including the dose consumed, gastric motility, presence of food in the stomach, concurrent use of a wide variety of drugs, and coexisting disease. Varying degrees of CNS tolerance to alcohol also can importantly modify the anticipated effect at any particular blood alcohol concentration.' In addition, the clinical features of acute intoxication largely depend on the rate at which a blood alcohol level has been attained as well as on the length of time it has been maintained. 2 Acute complications- The nonspecific depressant effect of ethanol on the nervous system can proceed to severe respiratory depression, resulting in death, at blood alcohol levels in the range of 400 to 700 mgj 100 ml. Intubation and mechanical ventilation will serve to maintain life until the alcohol level falls. Fortunately, hepatic metabolism of ethanol takes place rapidly and continued 133
Alcohol's effect on the CNS can lead to severe respiratory clepression and death. Intubation ;!lnd mechanical ventilation will malintain life until the alcohol level falls.
predictably, usually at a rate of '7 to 10 gm 1hr in an average adult. This corresponds to about 0.66 to 1 oz of ~proof spirits or 8 to I 2 oz of beer. The chronic alcohol abuser may metabolize ethanol at a rate that decreases the blood alcohol level up to 30 mg/ 100 ml/hr, compared with an hourly decrease of about 20 mg/ 100 ml in the nonabuser.2 As with any ill patient, a complete clinical assessment of the acutely intoxicated person is mandatory if the physician is to avoid overlooking important treatable disease. Alcohol intoxication may be accompanied by serious complications that may or may not be directl)' related to alcohol abuse. Metabolic encephalopathy may result from hypoglycemia, electrolyte and acid-base disturbances, and hepatic failure. In ac.dition, head injury is especially common in the alcohol abuser. In an unconscious person, determination of blood alcohol level can be of clinical assistance. When a discrepancy exists between this finding and the level
of consciousness, a prodigious search must be made for causes of coma other than alcohol ingestion. Treatment-Because of the rapidity of alcohol absorption, gastric lavage is of limited value except in cases involving concomitant overdosage with other drugs. In the intensive care unit the patient in alcohol coma should receive the usual attention and management afforded any comatose person. Administration of intravenous fluids and even pressor agents may be necessary, although there is doubt as to the value of analeptics such as nikethamide because of the increased risk of seizures, arrhythmias, and marked hypertension. It is wise to administer thiamine, 100 mg intramuscularly or intravenously, to avoid the possibility of precipitating the WernickeKorsakoff syndrome by the intravenous administration of glucose solutions. 3 Respiratory failure should be managed by tracheal intubation and mechanical ventilation, which will seldom be necessary for more than a number of hours because of relatively rapid ethanol metabolism. Concurrent overdosage with a drug or drugs that can be dialyzed, the occurrence of severe alcohol overdose in children, the presence of ethylene glycol or methanol, or the development of profound acidosis may necessitate hemodialysis. 4•5 Since alcohol acts on the lipid bulk phase of cell membranes in the same fashion as do general anesthetics, it is unlikely on theoretical grounds that a specific alcohol antagonist will be found. The only agent that has been shown to hasten the removal of alcohol is fructose; however, complications and side effects preclude its general application. 2 Alcohol withdrawal syndrome Clinical features-Abrupt cessation of alcohol intake after prolonged excessive consumption gives rise to a clinical syndrome of alcohol withdrawal, characterized by tremor, irritability, insomnia, anxiety, agitation, sensory hyperacuity, disorien-
134
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
Fructose is the only agent that has been shown to hasten removal of alcohol from the blood, but complications and side effects preclude its general use.
tation, hallucinations, diaphoresis, and reduction of seizure threshold. 6-s The clinical spectrum is remarkably variable. An accurate history of ethanol intake may enable the physician to anticipate the possibility of a withdrawal reaction. However, it is equally important to consider the diagnosis when even one of the characteristic signs or symptoms develops unexpectedly. Mild withdrawal syndrome usually consists of irritability, sleeplessness, and tremor that resolve within two days. Less commonly, severe tremulousness and auditory and I or visual· hallucinations may develop during the second or third day. If global confusion (person, place, time, thought) develops, a major withdrawal reaction or delirium tremens is diagnosed. Seizures typically occur within 60 hours of cessation of drinking. 9 On occasion the withdrawal syndrome may be characterized only by seizures or by an acute psychosis. The evolution of a "typical" case of untreated alcohol
withdrawal is illustrated in figure I. General treatment measures- Management of alcohol withdrawal involves the treatment of symptoms as well as recognition and treatment of complications. Attempts to introduce the patient into a rehabilitation program should be deferred until withdrawal is completed. A full clinical assessment is essential to identify concurrent diseases (eg, pneumonia, fever, general debility, and fluid and electrolyte disturbances) known to precipitate or increase the severity of the alcohol withdrawal syndrome. IO,II Persons with medical or surgical problems (eg, fever higher than 38 C; history of seizures, hallucinations, or major withdrawal syndrome) should be hospitalized. General treatment measures include having the patient nursed in a quiet but light environment. Thiamine is given in a single dose, 50 to I00 mg intramuscularly or by two-minute intravenous infusion. Administration of multivitamins is concontinued Figure I. Schematic representation of components and typical time course of signs and symptoms of alcohol withdrawal. Virtually any single sign or symptom can exist alone or in combination with any others. Major withdrawal syndrome typically takes three or four days to fully develop and is distinguished from minor withdrawal syndrome by appearance of global confusion. Variation among patients is pictorially summarized by broken lines. Severity of withdrawal symptom or sign is indicated by height of quadrangle.
VOL 64/NO 6/0ECEMBER 1978/POSTGRADUATE MEDICINE
135
The clinical spectrum of the alcohol withdrawal syndrome is remark· ably variable. The mild form is usually characteriznd by irritability, insomnia, nnd tremor; the severe form is marked by global confusion.
ventional although of unproven efficacy. The management of fluid and electrolyte abnormalities is no different in alcohol withdrawal than in other conditions. Suffice it to say that such abnormalities, often combined with acid-base imbalance, are very common .:md often complicated (eg, a patient with hypokalemia, respiratory failure, vomiting and dehydration, and lactic acidosis). The administration of alcohol may be inappropriate treatment because the dn;.g is far more toxic than alternate agents, the duration of action is short, and the alcohol-induced metabolic disturbances are perpetuated. An a,gent that exhibits cross-tolerance with ethanol might be expected to be of value in the treatment of withdrawal reactions. In the past few decades numerous agents have been proposed, but only a relatively small number have been demonstrably superior to placebo. This group includes antihistamines, benzodiazepines, barbiturates, clomethiazole, chloral hydrate, "major" tranquilizers (eg, chlorpromazine, thioridazine, haloperidol), and paraldehyde. 5,9,12 Benzodiazepine therapy- The benzodiazepines are at least as effective as other agents and
are less toxic. 2 Many benzodiazepine derivatives are currently available, including chlordiazepoxide, clorazepate, diazepam, flurazepam, oxazepam, and prazepam. All are of equal effect in equivalent doses, although chlordiazepoxide has been the most intensively studied and widely used in therapy for ethanol withdrawal reactions. (See table 1.) The formation of pharmacologically active derivatives of both diazepam and chlordiazepoxide, each of which has a long half-life, results in gradual accumulation with repeated daily dosage. This potential problem does not occur with oxazepam, which is converted into an inactive metabolite and has a half-life of eight hours. 13 Clorazepate is also subject to cumulation kinetics, because it is transformed into the same active derivative as diazepam, namely, desmethyldiazepam. Chlordiazepoxide is given in doses usually in the range of 100 to 400 mg on the first day, although on occasion the severity of withdrawal symptoms may require as much as 1,600 mg. To avoid the undesirable consequences of excessive CNS depression, such as confusion, ataxia, or even respiratory depression, the dose is gradually reduced on successive days. This drug is given Clive C. Robertson (left) Dr Robertson is a practicing general internist with specialist training at the Addiction Research Foundation, Toronto. Edward M. Sellers (right) Dr Sellers is associate professor of pharma. cology and of medicine, University of Toronto, and director, division of clinical pharmacology, Addiction Research Foundation and Toronto Western Hospital. His interests include protein binding, drug interactions, and applied pharmacokinetics.
136
VOL 64/NO 6/0ECEMBER 1978/POSTGRAOUATE MEDICINE
The benzodiazepines are at least as effective as other agents for treatment of alcohol withdrawal syndrome and are less toxic.
orally or intravenously for reliable and rapid effect, as both it and diazepam show poor bioavailability when administered intramuscularly. Dose reduction of chlordiazepoxide or diazepam may be required when severe liver disease is present, owing to higher free drug levels in patients with hypoalbuminemia and to decrease of drug clearance in those with cirrhosis. If the physician considers these problems in deciding dosage, the benzodiazepines are unlikely to produce excessive sedation and even less likely to produce physical dependence.IJ For the majority of patients, alcohol withdrawal reactions are minor and can be safely treated at home. Chlordiazepoxide is given orally, 50 to 100 mg, and after an observation period of several hours the patient can be allowed to go home with a prescription for chlordiazepoxide, 25 mg to be taken orally four times daily for four days. Propranolol therapy-Alcohol withdrawal is associated with increases in urine and plasma catecholamine levels, 10 and the clinical features suggest a hyperadrenergic state. Propranolol has been shown to be effective in reducing tremor, blood pressure, heart rate, and catecholamine lev-
els during alcohol withdrawal when given in doses of 40 mg orally four times daily. 14 This drug can be used in mild withdrawal reactions in patients without a history of withdrawal seizures, asthma, bronchospastic chronic obstructive airways disease, cardiomyopathy, or insulin-requiring diabetes. Treatment of alcoholic hallucinosis-Hallucinations can be a prominent feature of the alcohol withdrawal syndrome and may respond adequately to the use of benzodiazepines. The specific antihallucinatory properties of phenothiazine tranquilizers in alcoholic hallucinosis have not been proven. However, the butyrophenone tranquilizer haloperidol seems of value in treating alcoholic hallucinosis and severe agitation once the risk of seizures has diminished. It is usually given intramuscularly, as indicated in table I. Treatment of alcohol withdrawal seizuresAlcohol withdrawal seizures are usually of the nonfocal grand mal type and occur during the first two days after cessation of ethanol consumption. Repeated or continuous seizures should be treated pharmacologically. Diazepam as an intravenous infusion is effective in controlling continuous seizure activity. Benzodiazepines have continued
Table 1. Drug therapy In alcohol withdrawal syndrome Degree of withdrawal
Drug
Dosage
Mild or moderate
Chlordiazepoxide·
25-1 00 mg po, then 25 mg po q6h for 4 days
Severe 1. Without seizure history
Chlordiazepoxide·
IV infusion, 12.5 mg/min initially until patient calm
2. With history of previous seizures
Add phenytoin to (1)
100 mg po q8h if patient not taking phenytoin; 300 mg po initially, then 100 mg q8h if patient has taken phenytoin within 1 week
3. With repeated seizures
Phenytoin
10 mg/kg IV (not to exceed 50 mg/min), then 100 mg po q8h
4. W1th hallucinosis unresponsive to benzodiazepines
Haloperidol
0.5-2.0 mg IM q2h until satisfactory response (up to 5 doses)
·oiazepam can be substituted for chlordiazepoxide in 1/5 dose.
VOL 64/NO 6/0ECEMBER 1978/POSTGRADUATE MEDICINE
137
sufficient anticonvulsant activity to prevent the development of withdrawal seizures in persons with no history of seizures.l5,16 Treatment of patients with a. history of withdrawal seizures includes ad ministration of phenytoin in addition to chlordiazepoxide 15 (table I). Phenytoin is erratically and incompletely absorbed by the intramuscular ro llte and should be given orally or intravenously. Optimal results are obtained by administration of a loading dose of phenytoin, 10 mgj kg of body weight4 infused at a rate not exceeding 50 mgj min to avoid significant hypotension. Oral doses in the range of 100 mg three or four times daily are thm prescribed only for the duration of the withdrawal period. Patients with seizure at times other than during withdrawal should continue to receive anticonvulsants. Summary Careful medical assessment of alcohol-abusing patients is essential. General supportive care is usually sufficient treatment of alcohol intoxication. Determination of blood alcohol levels may assist in the clinical assessment oJ the unconscious intoxicated patient. The alcohol withdrawal synd.-ome is generally mlld and can be controlled by a benzodiazepine, such as chlordiazepoxide. Sevt~re reactions require hospitalization and oral or intravenous administration of a benzodiazepine. Other pharmacotherapy may includ•~ phenytoin for withdrawal seizures, haloperidol for severe agitation or hallucinations, or propranolol in selected patients.
References I. Kalant H, LeBianc AE, Gibbons R.J: Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacal Rev 23:135-191, 1971 2. Koch-Weser J, Sellers EM, Kalant H: Alcohol intoxication and withdrawal. N EngiJ Med 294:757-762, 1976 3. Greenblatt DJ, Shader RI: Treatment of the alcohol withdrawal syndrome. In Shader RI (Editor): Manual of Psychiatric Therapeutics: Practical Psychopharmacology and Psychiatry. Boston, Little Brown & Co, 1975, pp 211-235 4. Marc-Aurele J, Schreiner GE: The dialysance of ethanol and methanol: A proposed method for the treatment of massive intoxication by ethyl or methyl alcohol. J Clin Invest 39:802-807, 1960 5. Hawkins RD, Kalant H: The metabolism of ethanol and its metabolic effects. Pharmacal Rev 24:67-157, 1972 6. Victor M: Treatment of alcoholic intoxication and the withdrawal syndrome: A critical analysis of the drugs and other forms oftherapy. Psychosom Med 28:63CHi50, 1966 7. - - : The alcohol withdrawal syndrome: Theory and practice. Postgrad Med 47:68-72, Apr 1970 8. Gross MM, Lewis E, Hastey J: Acute alcohol withdrawal syndrome. In Kissin B, Begleiter H (Editors): Biology of Alcoholism Series. Vol3. Clinical Pathology. New York, Plenum Press, 1974, pp 191-263 9. Victor M, Brausch C: The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 8:1-20, 1967 10. Tavel ME, Davidson W, Batterton TO: A critical analysis of mortality associated with delirium tremens: Review of 39 fatalities in 9-year period. Am J Med Sci 242: 18-29, 1961 11. Jacob MS, Sellers EM: Emergency management of alcohol withdrawal. Drug Ther 7:28-34, Apr 1977 12. Greenblatt DJ, Greenblatt M: Which drug for alcohol withdrawal? J Clin Pharmacoll2:429-431, 1972 13. Greenblatt DJ, Shader RI (Editors): Benzodiazepines in Clinical Practice. New York, Raven Press, 1974 14. Sellers EM, Zilm OH, Degani NC: Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal. J Stud Alcohol38:2096-2108, 1977 15. Kaim SC, Klett CJ, Rothfield B: Treatment of the acute alcohol withdrawal state: A comparison of four drugs. Am J Psychiatry 125:1~1646, 1969 16. Sampliner R, Iber FL: Diphenylhydantoin control of alcohol withdrawal seizures: Results of a controlled study. JAMA 230:14»1432, 1974
Address reprint requests to E. M. Sellers, MD, 33 Russell St, Toronto, Ont, M5S 2SI, Canada. CME Credit Quiz begins oncpage 155.
138
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Alcohol intoxication and the alcohol withdrawal syndrome Clive C. Robertson BM, BCh & Edward M. Sellers MD, PhD To cite this article: Clive C. Robertson BM, BCh & Edward M. Sellers MD, PhD (1978) Alcohol intoxication and the alcohol withdrawal syndrome, Postgraduate Medicine, 64:6, 133-138, DOI: 10.1080/00325481.1978.11715005 To link to this article: http://dx.doi.org/10.1080/00325481.1978.11715005
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Newcastle, Australia]
Date: 26 December 2016, At: 12:39
Sixth of seven symposium articles in this issue
Alcohol intoxication and the alcohol withdrawal syndrome Consider How does the hepatic metabolism rate of ethanol in chronic alcohol abusers compare with that in nonabusers? What are the biochemical physiologic abnormalities that may produce metabolic encephalopathy in alcoholic patients? What signs and symptoms characterize the alcohol withdrawal syndrome?
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
Clive C. Robertson, BM, BCh Edward M. Sellers, MD, PhD
Although acute alcohol intoxication can cause death, hepatic metabolism of ethanol is usually rapid, and in most cases general supportive care of the intoxicated patient is all that is required. Abrupt cessation of prolonged excessive alcohol intake gives rise to the alcohol withdrawal syndrome. The fundamentals of treatment are careful assessment of the patient and judicious use of a benzodiazepine. Alcohol intoxication and in particular the alcohol withdrawal syndrome constitute two important medical components of the major public health problem of alcoholism. The long-term treatment of alcohol abuse largely involves sociobehavioral approaches. This discussion is restricted to consideration of intoxication and the consequences of abrupt cessation of alcohol intake, both of which may produce significant morbidity and even mortality. Alcohol intoxication Clinical features- The clinical picture of acute alcohol intoxication is influenced by various factors, including the dose consumed, gastric motility, presence of food in the stomach, concurrent use of a wide variety of drugs, and coexisting disease. Varying degrees of CNS tolerance to alcohol also can importantly modify the anticipated effect at any particular blood alcohol concentration.' In addition, the clinical features of acute intoxication largely depend on the rate at which a blood alcohol level has been attained as well as on the length of time it has been maintained. 2 Acute complications- The nonspecific depressant effect of ethanol on the nervous system can proceed to severe respiratory depression, resulting in death, at blood alcohol levels in the range of 400 to 700 mgj 100 ml. Intubation and mechanical ventilation will serve to maintain life until the alcohol level falls. Fortunately, hepatic metabolism of ethanol takes place rapidly and continued 133
Alcohol's effect on the CNS can lead to severe respiratory clepression and death. Intubation ;!lnd mechanical ventilation will malintain life until the alcohol level falls.
predictably, usually at a rate of '7 to 10 gm 1hr in an average adult. This corresponds to about 0.66 to 1 oz of ~proof spirits or 8 to I 2 oz of beer. The chronic alcohol abuser may metabolize ethanol at a rate that decreases the blood alcohol level up to 30 mg/ 100 ml/hr, compared with an hourly decrease of about 20 mg/ 100 ml in the nonabuser.2 As with any ill patient, a complete clinical assessment of the acutely intoxicated person is mandatory if the physician is to avoid overlooking important treatable disease. Alcohol intoxication may be accompanied by serious complications that may or may not be directl)' related to alcohol abuse. Metabolic encephalopathy may result from hypoglycemia, electrolyte and acid-base disturbances, and hepatic failure. In ac.dition, head injury is especially common in the alcohol abuser. In an unconscious person, determination of blood alcohol level can be of clinical assistance. When a discrepancy exists between this finding and the level
of consciousness, a prodigious search must be made for causes of coma other than alcohol ingestion. Treatment-Because of the rapidity of alcohol absorption, gastric lavage is of limited value except in cases involving concomitant overdosage with other drugs. In the intensive care unit the patient in alcohol coma should receive the usual attention and management afforded any comatose person. Administration of intravenous fluids and even pressor agents may be necessary, although there is doubt as to the value of analeptics such as nikethamide because of the increased risk of seizures, arrhythmias, and marked hypertension. It is wise to administer thiamine, 100 mg intramuscularly or intravenously, to avoid the possibility of precipitating the WernickeKorsakoff syndrome by the intravenous administration of glucose solutions. 3 Respiratory failure should be managed by tracheal intubation and mechanical ventilation, which will seldom be necessary for more than a number of hours because of relatively rapid ethanol metabolism. Concurrent overdosage with a drug or drugs that can be dialyzed, the occurrence of severe alcohol overdose in children, the presence of ethylene glycol or methanol, or the development of profound acidosis may necessitate hemodialysis. 4•5 Since alcohol acts on the lipid bulk phase of cell membranes in the same fashion as do general anesthetics, it is unlikely on theoretical grounds that a specific alcohol antagonist will be found. The only agent that has been shown to hasten the removal of alcohol is fructose; however, complications and side effects preclude its general application. 2 Alcohol withdrawal syndrome Clinical features-Abrupt cessation of alcohol intake after prolonged excessive consumption gives rise to a clinical syndrome of alcohol withdrawal, characterized by tremor, irritability, insomnia, anxiety, agitation, sensory hyperacuity, disorien-
134
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
Fructose is the only agent that has been shown to hasten removal of alcohol from the blood, but complications and side effects preclude its general use.
tation, hallucinations, diaphoresis, and reduction of seizure threshold. 6-s The clinical spectrum is remarkably variable. An accurate history of ethanol intake may enable the physician to anticipate the possibility of a withdrawal reaction. However, it is equally important to consider the diagnosis when even one of the characteristic signs or symptoms develops unexpectedly. Mild withdrawal syndrome usually consists of irritability, sleeplessness, and tremor that resolve within two days. Less commonly, severe tremulousness and auditory and I or visual· hallucinations may develop during the second or third day. If global confusion (person, place, time, thought) develops, a major withdrawal reaction or delirium tremens is diagnosed. Seizures typically occur within 60 hours of cessation of drinking. 9 On occasion the withdrawal syndrome may be characterized only by seizures or by an acute psychosis. The evolution of a "typical" case of untreated alcohol
withdrawal is illustrated in figure I. General treatment measures- Management of alcohol withdrawal involves the treatment of symptoms as well as recognition and treatment of complications. Attempts to introduce the patient into a rehabilitation program should be deferred until withdrawal is completed. A full clinical assessment is essential to identify concurrent diseases (eg, pneumonia, fever, general debility, and fluid and electrolyte disturbances) known to precipitate or increase the severity of the alcohol withdrawal syndrome. IO,II Persons with medical or surgical problems (eg, fever higher than 38 C; history of seizures, hallucinations, or major withdrawal syndrome) should be hospitalized. General treatment measures include having the patient nursed in a quiet but light environment. Thiamine is given in a single dose, 50 to I00 mg intramuscularly or by two-minute intravenous infusion. Administration of multivitamins is concontinued Figure I. Schematic representation of components and typical time course of signs and symptoms of alcohol withdrawal. Virtually any single sign or symptom can exist alone or in combination with any others. Major withdrawal syndrome typically takes three or four days to fully develop and is distinguished from minor withdrawal syndrome by appearance of global confusion. Variation among patients is pictorially summarized by broken lines. Severity of withdrawal symptom or sign is indicated by height of quadrangle.
VOL 64/NO 6/0ECEMBER 1978/POSTGRADUATE MEDICINE
135
The clinical spectrum of the alcohol withdrawal syndrome is remark· ably variable. The mild form is usually characteriznd by irritability, insomnia, nnd tremor; the severe form is marked by global confusion.
ventional although of unproven efficacy. The management of fluid and electrolyte abnormalities is no different in alcohol withdrawal than in other conditions. Suffice it to say that such abnormalities, often combined with acid-base imbalance, are very common .:md often complicated (eg, a patient with hypokalemia, respiratory failure, vomiting and dehydration, and lactic acidosis). The administration of alcohol may be inappropriate treatment because the dn;.g is far more toxic than alternate agents, the duration of action is short, and the alcohol-induced metabolic disturbances are perpetuated. An a,gent that exhibits cross-tolerance with ethanol might be expected to be of value in the treatment of withdrawal reactions. In the past few decades numerous agents have been proposed, but only a relatively small number have been demonstrably superior to placebo. This group includes antihistamines, benzodiazepines, barbiturates, clomethiazole, chloral hydrate, "major" tranquilizers (eg, chlorpromazine, thioridazine, haloperidol), and paraldehyde. 5,9,12 Benzodiazepine therapy- The benzodiazepines are at least as effective as other agents and
are less toxic. 2 Many benzodiazepine derivatives are currently available, including chlordiazepoxide, clorazepate, diazepam, flurazepam, oxazepam, and prazepam. All are of equal effect in equivalent doses, although chlordiazepoxide has been the most intensively studied and widely used in therapy for ethanol withdrawal reactions. (See table 1.) The formation of pharmacologically active derivatives of both diazepam and chlordiazepoxide, each of which has a long half-life, results in gradual accumulation with repeated daily dosage. This potential problem does not occur with oxazepam, which is converted into an inactive metabolite and has a half-life of eight hours. 13 Clorazepate is also subject to cumulation kinetics, because it is transformed into the same active derivative as diazepam, namely, desmethyldiazepam. Chlordiazepoxide is given in doses usually in the range of 100 to 400 mg on the first day, although on occasion the severity of withdrawal symptoms may require as much as 1,600 mg. To avoid the undesirable consequences of excessive CNS depression, such as confusion, ataxia, or even respiratory depression, the dose is gradually reduced on successive days. This drug is given Clive C. Robertson (left) Dr Robertson is a practicing general internist with specialist training at the Addiction Research Foundation, Toronto. Edward M. Sellers (right) Dr Sellers is associate professor of pharma. cology and of medicine, University of Toronto, and director, division of clinical pharmacology, Addiction Research Foundation and Toronto Western Hospital. His interests include protein binding, drug interactions, and applied pharmacokinetics.
136
VOL 64/NO 6/0ECEMBER 1978/POSTGRAOUATE MEDICINE
The benzodiazepines are at least as effective as other agents for treatment of alcohol withdrawal syndrome and are less toxic.
orally or intravenously for reliable and rapid effect, as both it and diazepam show poor bioavailability when administered intramuscularly. Dose reduction of chlordiazepoxide or diazepam may be required when severe liver disease is present, owing to higher free drug levels in patients with hypoalbuminemia and to decrease of drug clearance in those with cirrhosis. If the physician considers these problems in deciding dosage, the benzodiazepines are unlikely to produce excessive sedation and even less likely to produce physical dependence.IJ For the majority of patients, alcohol withdrawal reactions are minor and can be safely treated at home. Chlordiazepoxide is given orally, 50 to 100 mg, and after an observation period of several hours the patient can be allowed to go home with a prescription for chlordiazepoxide, 25 mg to be taken orally four times daily for four days. Propranolol therapy-Alcohol withdrawal is associated with increases in urine and plasma catecholamine levels, 10 and the clinical features suggest a hyperadrenergic state. Propranolol has been shown to be effective in reducing tremor, blood pressure, heart rate, and catecholamine lev-
els during alcohol withdrawal when given in doses of 40 mg orally four times daily. 14 This drug can be used in mild withdrawal reactions in patients without a history of withdrawal seizures, asthma, bronchospastic chronic obstructive airways disease, cardiomyopathy, or insulin-requiring diabetes. Treatment of alcoholic hallucinosis-Hallucinations can be a prominent feature of the alcohol withdrawal syndrome and may respond adequately to the use of benzodiazepines. The specific antihallucinatory properties of phenothiazine tranquilizers in alcoholic hallucinosis have not been proven. However, the butyrophenone tranquilizer haloperidol seems of value in treating alcoholic hallucinosis and severe agitation once the risk of seizures has diminished. It is usually given intramuscularly, as indicated in table I. Treatment of alcohol withdrawal seizuresAlcohol withdrawal seizures are usually of the nonfocal grand mal type and occur during the first two days after cessation of ethanol consumption. Repeated or continuous seizures should be treated pharmacologically. Diazepam as an intravenous infusion is effective in controlling continuous seizure activity. Benzodiazepines have continued
Table 1. Drug therapy In alcohol withdrawal syndrome Degree of withdrawal
Drug
Dosage
Mild or moderate
Chlordiazepoxide·
25-1 00 mg po, then 25 mg po q6h for 4 days
Severe 1. Without seizure history
Chlordiazepoxide·
IV infusion, 12.5 mg/min initially until patient calm
2. With history of previous seizures
Add phenytoin to (1)
100 mg po q8h if patient not taking phenytoin; 300 mg po initially, then 100 mg q8h if patient has taken phenytoin within 1 week
3. With repeated seizures
Phenytoin
10 mg/kg IV (not to exceed 50 mg/min), then 100 mg po q8h
4. W1th hallucinosis unresponsive to benzodiazepines
Haloperidol
0.5-2.0 mg IM q2h until satisfactory response (up to 5 doses)
·oiazepam can be substituted for chlordiazepoxide in 1/5 dose.
VOL 64/NO 6/0ECEMBER 1978/POSTGRADUATE MEDICINE
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sufficient anticonvulsant activity to prevent the development of withdrawal seizures in persons with no history of seizures.l5,16 Treatment of patients with a. history of withdrawal seizures includes ad ministration of phenytoin in addition to chlordiazepoxide 15 (table I). Phenytoin is erratically and incompletely absorbed by the intramuscular ro llte and should be given orally or intravenously. Optimal results are obtained by administration of a loading dose of phenytoin, 10 mgj kg of body weight4 infused at a rate not exceeding 50 mgj min to avoid significant hypotension. Oral doses in the range of 100 mg three or four times daily are thm prescribed only for the duration of the withdrawal period. Patients with seizure at times other than during withdrawal should continue to receive anticonvulsants. Summary Careful medical assessment of alcohol-abusing patients is essential. General supportive care is usually sufficient treatment of alcohol intoxication. Determination of blood alcohol levels may assist in the clinical assessment oJ the unconscious intoxicated patient. The alcohol withdrawal synd.-ome is generally mlld and can be controlled by a benzodiazepine, such as chlordiazepoxide. Sevt~re reactions require hospitalization and oral or intravenous administration of a benzodiazepine. Other pharmacotherapy may includ•~ phenytoin for withdrawal seizures, haloperidol for severe agitation or hallucinations, or propranolol in selected patients.
References I. Kalant H, LeBianc AE, Gibbons R.J: Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacal Rev 23:135-191, 1971 2. Koch-Weser J, Sellers EM, Kalant H: Alcohol intoxication and withdrawal. N EngiJ Med 294:757-762, 1976 3. Greenblatt DJ, Shader RI: Treatment of the alcohol withdrawal syndrome. In Shader RI (Editor): Manual of Psychiatric Therapeutics: Practical Psychopharmacology and Psychiatry. Boston, Little Brown & Co, 1975, pp 211-235 4. Marc-Aurele J, Schreiner GE: The dialysance of ethanol and methanol: A proposed method for the treatment of massive intoxication by ethyl or methyl alcohol. J Clin Invest 39:802-807, 1960 5. Hawkins RD, Kalant H: The metabolism of ethanol and its metabolic effects. Pharmacal Rev 24:67-157, 1972 6. Victor M: Treatment of alcoholic intoxication and the withdrawal syndrome: A critical analysis of the drugs and other forms oftherapy. Psychosom Med 28:63CHi50, 1966 7. - - : The alcohol withdrawal syndrome: Theory and practice. Postgrad Med 47:68-72, Apr 1970 8. Gross MM, Lewis E, Hastey J: Acute alcohol withdrawal syndrome. In Kissin B, Begleiter H (Editors): Biology of Alcoholism Series. Vol3. Clinical Pathology. New York, Plenum Press, 1974, pp 191-263 9. Victor M, Brausch C: The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 8:1-20, 1967 10. Tavel ME, Davidson W, Batterton TO: A critical analysis of mortality associated with delirium tremens: Review of 39 fatalities in 9-year period. Am J Med Sci 242: 18-29, 1961 11. Jacob MS, Sellers EM: Emergency management of alcohol withdrawal. Drug Ther 7:28-34, Apr 1977 12. Greenblatt DJ, Greenblatt M: Which drug for alcohol withdrawal? J Clin Pharmacoll2:429-431, 1972 13. Greenblatt DJ, Shader RI (Editors): Benzodiazepines in Clinical Practice. New York, Raven Press, 1974 14. Sellers EM, Zilm OH, Degani NC: Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal. J Stud Alcohol38:2096-2108, 1977 15. Kaim SC, Klett CJ, Rothfield B: Treatment of the acute alcohol withdrawal state: A comparison of four drugs. Am J Psychiatry 125:1~1646, 1969 16. Sampliner R, Iber FL: Diphenylhydantoin control of alcohol withdrawal seizures: Results of a controlled study. JAMA 230:14»1432, 1974
Address reprint requests to E. M. Sellers, MD, 33 Russell St, Toronto, Ont, M5S 2SI, Canada. CME Credit Quiz begins oncpage 155.
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