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Copyright The McGraw-Hill Companies. All rights reserved. Harrison's Internal Medicine > Chapter 387. Alcohol and Alcoholism > Alcohol and Alcoholism: Introduction Alcohol, a drug, is consumed at some time by up to 80% of the population. At low doses alcohol can have some beneficial effects such as decreased rates of myoca rdial infarction, stroke, gallstones, and possibly vascular and Alzheimer's deme ntias. However, the consumption of more than two standard drinks per day increas es the risk for health problems in many organ systems. Heavy repetitive drinking , as is seen in alcohol abuse and dependence, cuts short the life span by an est imated decade in both genders, all cultural groups, and all socioeconomic strata . Unless an individual stops drinking, a diagnosis of alcohol dependence carries a 80% risk for continued severe problems over the next 5 years. In addition, ev en relatively low doses of alcohol can adversely affect many preexisting disease states and alter the effectiveness or blood levels of most over-the-counter and prescribed medications. Pharmacology and Nutritional Impact of Ethanol Ethanol is a weakly charged molecule that moves easily through cell membranes, r apidly equilibrating between blood and tissues. The level of alcohol in the bloo d is expressed as milligrams or grams of ethanol per deciliter (e.g., 100 mg/dL or 0.10 g/dL), with blood values of about 0.02 g/dL resulting from the ingestion of one typical drink. In round figures, 340 mL (12 oz) of beer, 115 mL (4 oz) o f nonfortified wine, and 43 mL (1.5 oz) (a shot) of 80-proof beverage such as wh isky, gin, or vodka each contain ~10 15 g of ethanol; 0.5 L (1 pint) of 80-proof b everage contains ~160 g (about 16 standard drinks), and 1 L of wine contains ~80 g of ethanol. These beverages also have additional components, called congeners , that affect the taste and effects; congeners include low-molecular-weight alco hols (e.g., methanol and butanol), aldehydes, esters, histamine, phenols, tannin s, iron, lead, and cobalt. Such congeners might also contribute to the adverse h ealth consequences associated with heavy drinking. Ethanol is a central nervous system (CNS) depressant that decreases neuronal act ivity, although some behavioral stimulation is observed at low blood levels. Thi s drug has cross-tolerance with other depressants, including benzodiazepines and barbiturates, and all produce similar behavioral alterations. Alcohol is absorb ed from mucous membranes of the mouth and esophagus (in small amounts), from the stomach and large bowel (in modest amounts), and from the proximal portion of t he small intestine (the major site). The rate of absorption is increased by rapi d gastric emptying (as can be induced by carbonated beverages); by the absence o f proteins, fats, or carbohydrates (which interfere with absorption); by the abs ence of congeners; and by dilution to a modest percentage of ethanol (maximum at ~20% by volume). Between 2% (at low blood alcohol concentrations) and 10% (at high blood alcohol concentrations) of ethanol is excreted directly through the lungs, urine, or swe at, but the greater part is metabolized to acetaldehyde, primarily in the liver. The most important pathway occurs in the cell cytosol where alcohol dehydrogena se (ADH) produces acetaldehyde, which is then rapidly destroyed by aldehyde dehy drogenase (ALDH) in the cytosol and mitochondria (Fig. 387-1). A second pathway

in the microsomes of the smooth endoplasmic reticulum (the microsomal ethanol-ox idizing system, or MEOS), is responsible for 10% of ethanol oxidation at high bl ood alcohol concentrations. Figure 387-1

The metabolism of alcohol. MEOS, microsomal ethanol-oxidizing system.

While alcohol supplies calories (a drink contains ~300 kJ, or 70 100 kcal), these are devoid of nutrients such as minerals, proteins, and vitamins. Alcohol can al so interfere with absorption of vitamins in the small intestine and decreases th eir storage in the liver with modest effects on folate (folacin or folic acid), pyridoxine (B6), thiamine (B1), nicotinic acid (niacin, B3), and vitamin A. An ethanol load in a fasting, healthy individual is likely to produce transient hypoglycemia within 6 36 h, secondary to the acute actions of ethanol on gluconeog enesis. This can temporarily result in abnormal glucose tolerance tests (with a resulting erroneous diagnosis of diabetes mellitus) until the alcoholic has abst ained for 2 4 weeks. Alcohol ketoacidosis, probably reflecting a decrease in fatty acid oxidation coupled with poor diet or recurrent vomiting, can be misdiagnose d as diabetic ketosis. With the former, patients show an increase in serum keton es along with a mild increase in glucose but a large anion gap, a mild to modera te increase in serum lactate, and a -hydroxybutyrate/lactate ratio of between 2: 1 and 9:1 (with normal being 1:1). Behavioral Effects, Tolerance, and Dependence The acute effects of a drug depend on many factors. These include the dose, the rate of increase in plasma, the concomitant presence of other drugs, and the pas t experience with the agent. With alcohol, an additional factor is whether blood alcohol levels are rising or falling; the effects are more intense during the f ormer period. "Legal intoxication" in the United States requires a blood alcohol concentration of at least 0.08 0.10 g/dL, while levels of 0.04 or even lower are cited in some other countries. However, behavioral, psychomotor, and cognitive changes are see n at levels as low as 0.02 0.03 g/dL (i.e., after one to two drinks) (Table 387-1) . Deep but disturbed sleep can be seen at twice the legal intoxication level, an d death can occur with levels between 0.30 and 0.40 g/dL. Beverage alcohol is pr obably responsible for more overdose deaths than any other drug. Table 387-1 Effects of Blood Alcohol Levels in the Absence of Tolerance

Blood Level, g/dL Usual Effect 0.02 Decreased inhibitions, a slight feeling of intoxication 0.08 Decrease in complex cognitive functions and motor performance 0.20 Obvious slurred speech, motor incoordination, irritability, and poor judgme nt 0.30 Light coma and depressed vital signs 0.40 Death

The intoxicating effects of alcohol reflect the actions of this drug on a wide r ange of neurotransmitters, receptors, and transporters. Most prominently, alcoho l acutely enhances actions at -aminobutyric acid A (GABAA) receptors and inhibit s N-methyl-D-aspartate (NMDA) receptors. There are also effects on adenosine, wi th an inhibition of uptake of this transmitter, and a translocation of the cycli c AMP dependent protein kinase catalytic subunit from the cytoplasm to the nucleus . Alcohol also affects opioid systems and cannabinol receptors, enhances activit y of the dopamine-rich reward system, increases serotonin actions, and directly or indirectly affects most other neurochemical systems. As with most depressants , neurons adapt quickly to these actions, and tolerance to many effects develops ; after repeated exposure, abrupt decreases in blood alcohol levels are likely t o produce physiologic changes that are opposite to the acute effects of this dru g (i.e., withdrawal). The presence of tolerance and/or withdrawal characterizes physical dependence. Tolerance is a complex phenomenon involving at least three types of compensatory mechanisms. (1) After 1 2 weeks of daily drinking, metabolic or pharmacokinetic t olerance can be seen, with up to a 30% increase in the rate of hepatic ethanol m etabolism. This alteration disappears almost as rapidly as it develops. (2) Cell ular or pharmacodynamic tolerance develops through neurochemical changes that ma intain relatively normal physiologic functioning despite the presence of alcohol . Subsequent decreases in blood levels contribute to symptoms of withdrawal. (3) Individuals learn to adapt their behavior so that they can function better than expected under influence of the drug (behavioral tolerance). The cellular changes caused by chronic ethanol exposure may not resolve for seve ral weeks or longer following cessation of drinking. The resulting withdrawal sy ndrome is most intense during the first 5 days, but some symptoms (e.g., disturb ed sleep and anxiety) can take up to 4 6 months to resolve. The Effects of Ethanol on Organ Systems Although one to two drinks per day in an otherwise healthy and nonpregnant indiv idual can have some beneficial cardiovascular effects, at higher doses alcohol i s toxic to most organ systems. Knowledge about the deleterious effects of alcoho l helps the physician to identify alcoholic patients and provides information th at can be used to help motivate patients to abstain. The information offered her e generally applies to all, regardless of age or gender, although some differenc es apply. It is important to remember that the typical white- or blue-collar alc oholic often functions at a fairly high level for years, holding a job and maint aining ties with friends and relatives who may be unaware of the severity of the drinking problem. Not everyone develops each of the problems described below. Nervous System Approximately 35% of drinkers (and a much higher proportion of alcoholics) exper ience a blackout, an episode of temporary anterograde amnesia, in which the pers on forgets all or part of what occurred during a drinking evening. Another commo n problem, one seen after as few as several drinks, is disturbed sleep. Although alcohol might initially help a person to fall asleep, it disrupts sleep through out the rest of the night. The stages of sleep are also altered, and time spent in rapid eye movement (REM) and deep sleep is reduced. Patients may experience p rominent and sometimes disturbing dreams. Alcohol relaxes muscles in the pharynx , which can cause snoring and exacerbate sleep apnea; symptoms of the latter occ ur in 75% of alcoholic men over age 60. Another common consequence of alcohol us e is impaired judgment and coordination, increasing the risk of accidents and in jury; 40% of drinkers in the United States have at some time driven while intoxi cated. Heavy drinking can also be associated with headache, thirst, nausea, vomi ting, and fatigue the following day, a hangover syndrome that is responsible for

significant financial losses in most work environments. The effect of alcohol on the nervous system is even more pronounced among alcoho l-dependent individuals. Chronic high doses cause peripheral neuropathy in 5 15% o f alcoholics: similar to diabetes, patients experience bilateral limb numbness, tingling, and paresthesias, all of which are more pronounced distally. Approxima tely 1% of alcoholics develop cerebellar degeneration or atrophy. This is a synd rome of progressive unsteady stance and gait often accompanied by mild nystagmus ; neuroimaging studies reveal atrophy of the cerebellar vermis. Fortunately, ver y few alcoholics (perhaps as few as 1 in 500) develop Wernicke's (ophthalmopares is, ataxia, and encephalopathy) and Korsakoff's (retrograde and anterograde amne sia) syndromes. These occur as the result of thiamine deficiency, especially in predisposed individuals, e.g., those with transketolase deficiency. Alcoholics c an manifest cognitive problems lasting for weeks to months after an alcoholic bi nge. Brain atrophy, evident as ventricular enlargement and widened cortical sulc i on MRI and CT scans, occurs in ~50% of chronic alcoholics; these changes are o ften reversible if abstinence is maintained. There is no single alcoholic dement ia syndrome; rather, this label is used to describe patients who have apparently irreversible cognitive changes (possibly from diverse causes) in the context of chronic alcoholism. As many as two-thirds of alcohol-dependent individuals meet the criteria for a p sychiatric syndrome in the Fourth Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association (Chap. 386). Half of these relate to a pree xisting antisocial personality manifesting as impulsivity and disinhibition. The lifetime risk is 3% in males, and 80% of such individuals demonstrate alcohol a nd/or drug dependence. Another common co-morbidity occurs with dependence on ill icit substances. The remaining third of alcoholics with psychiatric syndromes ha ve preexisting conditions such as schizophrenia or manic depressive disease and anxiety disorders such as panic disorder. The reasons for the co-morbidities of alcoholism with independent psychiatric disorders are not known, but they might represent an overlap in genetic vulnerabilities, impaired judgment resulting fro m the independent psychiatric condition, or an attempt to use alcohol to allevia te some of the symptoms of the disorder or side effects of medications. Many psychiatric syndromes can be seen temporarily during heavy drinking and sub sequent withdrawal. These include an intense sadness lasting for days to weeks i n the midst of heavy drinking seen in 40% of alcoholics (alcohol-induced mood di sorder); temporary severe anxiety in 10 30% of alcoholics, often beginning during alcohol withdrawal, and which can persist for a month or more after cessation of drinking (alcohol-induced anxiety disorder); and auditory hallucinations and/or paranoid delusions in a person who is alert and oriented, seen in 3 5% of alcohol ics (alcohol-induced psychotic disorder). Treatment of all forms of alcohol-induced psychopathology includes helping patie nts achieve abstinence and offering supportive care, as well as reassurance and "talk therapy" such as cognitive-behavioral approaches. However, with the except ion of short-term antipsychotics for substance-induced psychosis, substance-indu ced psychiatric conditions only rarely require medications. Recovery is likely w ithin several days to 4 weeks of abstinence. A history of alcohol intake is an i mportant consideration in any patient with one of these psychiatric symptoms. The distinction between long term, independent psychiatric conditions and tempor ary alcohol-induced syndromes is important because their prognoses and optimal t reatments are quite different. Independent syndromes can be recognized because t hey often began before the alcohol dependence and/or remain after a period of a month or more of abstinence. The Gastrointestinal System

Esophagus and Stomach Alcohol intake can result in inflammation of the esophagus and stomach causing e pigastric distress and gastrointestinal bleeding. Alcohol is one of the most com mon causes of hemorrhagic gastritis. Violent vomiting can produce severe bleedin g through a Mallory-Weiss lesion, a longitudinal tear in the mucosa at the gastr oesophageal junction. Pancreas and Liver The incidence of acute pancreatitis (~25 per 1000 per year) is almost threefold higher in alcoholics than in the general population, accounting for an estimated 10% or more of the total cases. Alcohol impairs gluconeogenesis in the liver, r esulting in a fall in the amount of glucose produced from glycogen, increased la ctate production, and decreased oxidation of fatty acids. This contributes to an increase in fat accumulation in liver cells. In healthy individuals these chang es are reversible, but with repeated exposure to ethanol, more severe changes in the liver occur, including alcohol-induced hepatitis, perivenular sclerosis, an d cirrhosis, with the latter observed in an estimated 15% of alcoholics (Chap. 3 01). Cancer Drinking as few as 1.5 drinks per day increases a woman's risk of breast cancer 1.4-fold. For both genders, four drinks per day increases the risk for oral and esophageal cancers approximately threefold and rectal cancers by a factor of 1.5 ; seven to eight or more drinks per day enhances approximately fivefold the risk s for many cancers. Hematopoietic System Ethanol causes an increase in red blood cell size [mean corpuscular volume, (MCV )], which reflects its effects on stem cells. If heavy drinking is accompanied b y folic acid deficiency, there can also be hypersegmented neutrophils, reticuloc ytopenia, and a hyperplastic bone marrow; if malnutrition is present, sideroblas tic changes can be observed. Chronic heavy drinking can decrease production of w hite blood cells, decrease granulocyte mobility and adherence, and impair delaye d-hypersensitivity responses to novel antigens (with a possible false-negative t uberculin skin test). Finally, many alcoholics have mild thrombocytopenia, which usually resolves within a week of abstinence unless there is hepatic cirrhosis or congestive splenomegaly. Cardiovascular System Acutely, ethanol decreases myocardial contractility and causes peripheral vasodi lation, with a resulting mild decrease in blood pressure and a compensatory incr ease in cardiac output. Exercise-induced increases in cardiac oxygen consumption are higher after alcohol intake. These acute effects have little clinical signi ficance for the average healthy drinker but can be problematic in men and women with persisting cardiac disease. The consumption of three or more drinks per day results in a dose-dependent incr ease in blood pressure, which returns to normal within weeks of abstinence. Thus , heavy drinking is an important factor in mild to moderate hypertension. Chroni c heavy drinkers have a sixfold increased risk for coronary artery disease as we ll as an increased risk for cardiomyopathy. Symptoms range from unexplained arrh ythmias in the presence of left ventricular impairment to heart failure with dil ation of all four heart chambers and hypocontractility of heart muscle. Perhaps one-third of cases of cardiomyopathy are alcohol-induced. Mural thrombi can form in the left atrium or ventricle, while heart enlargement >25% can cause mitral

regurgitation. Atrial or ventricular arrhythmias, especially paroxysmal tachycar dia, can also occur after a drinking binge in individuals showing no other evide nce of heart disease a syndrome known as the "holiday heart." This condition is ob served transiently in the majority of alcoholics entering treatment. Chronic intake of modest doses of alcohol can have some beneficial effects. A ma ximum of one to two drinks per day may decrease the risk for cardiovascular deat h, perhaps through an increase in high-density lipoprotein (HDL) cholesterol or changes in clotting mechanisms. In one large national study, cardiovascular mort ality was reduced by 30 40% among individuals reporting one or more drinks daily c ompared to nondrinkers, with overall mortality lowest among those consuming appr oximately one drink per day. Recent data have also corroborated that regular lig ht drinking decreases the risk for ischemic, but not hemorrhagic, stroke. Genitourinary System Changes, Sexual Functioning, and Fetal Development Acutely, modest ethanol doses (e.g., blood alcohol concentrations of 0.06 gm/dL) can increase sexual drive but also decrease erectile capacity in men. Even in t he absence of liver impairment, a significant minority of chronic alcoholic men show irreversible testicular atrophy with shrinkage of the seminiferous tubules, decreases in ejaculate volume, and a lower sperm count (Chap. 340). The repeated ingestion of high doses of ethanol by women can result in amenorrhe a, a decrease in ovarian size, absence of corpora lutea with associated infertil ity, and an increased risk of spontaneous abortion. Heavy drinking during pregna ncy results in the rapid placental transfer of both ethanol and acetaldehyde, wh ich may have serious consequences for fetal development. The fetal alcohol syndr ome can include any of the following: facial changes with epicanthal eye folds; poorly formed ear concha; small teeth with faulty enamel; cardiac atrial or vent ricular septal defects; an aberrant palmar crease and limitation in joint moveme nt; and microcephaly with mental retardation. The amount of ethanol required and the time of vulnerability during pregnancy have not been defined, making it adv isable for pregnant women to abstain completely. Other Effects of Ethanol Between one-half and two-thirds of alcoholics have skeletal muscle weakness caus ed by acute alcoholic myopathy, a condition that improves but which might not fu lly remit with abstinence. Effects of repeated heavy drinking on the skeletal sy stem include changes in calcium metabolism, lower bone density, and decreased gr owth in the epiphyses, leading to an increased risk for fractures and osteonecro sis of the femoral head. Hormonal changes include an increase in cortisol levels , which can remain elevated during heavy drinking; inhibition of vasopressin sec retion at rising blood alcohol concentrations and enhanced secretion at falling blood alcohol concentrations (with the final result that most alcoholics are lik ely to be slightly overhydrated); a modest and reversible decrease in serum thyr oxine (T4); and a more marked decrease in serum triiodothyronine (T3). Hormone i rregularities should be reevaluated after a month of abstinence. Alcoholism (Alcohol Abuse or Dependence) Because many drinkers occasionally imbibe to excess, temporary alcohol-related p athology is common in nonalcoholics, especially those in the late teens to the l ate twenties. When repeated problems in multiple life areas develop, the individ ual is likely to meet criteria for alcohol abuse or dependence. Definitions and Epidemiology Alcohol dependence is defined in DSM-IV as repeated alcohol-related difficulties in at least three of seven areas of functioning that cluster together over a 12

-month period. Two of these seven items, tolerance and withdrawal, may have spec ial importance as they are associated with a more severe clinical course. Alcoho l dependence is seen in all countries where alcohol is available and occurs in m en and women from all socioeconomic strata and all racial backgrounds. The diagn osis of alcohol dependence predicts a course of recurrent problems with the use of alcohol and the consequent shortening of the life span by a decade on average . Alcohol abuse is defined as repetitive problems with alcohol in any one of four life areas social, interpersonal, legal, and occupational or repeated use in hazardo us situations such as driving while intoxicated. If an individual is not alcohol dependent, he or she still may be given a diagnosis of alcohol abuse. The lifetime risk for alcohol dependence in most western countries is about 10 15% for men and 5 8% for women. Rates are generally similar in the United States, Can ada, Germany, Australia, and England; rates tend to be lower in most Mediterrane an countries, such as Italy, Greece, and Israel, and may be higher in Ireland, F rance, and Scandinavia. Even higher rates have been reported for several native cultures including American Indians, Eskimos, Maori groups, and aboriginal tribe s of Australia. These differences reflect both cultural and genetic influences, as described below. When alcohol abuse is also considered, the rates of alcohol use disorders increase. In western countries, the typical alcoholic does not ful fill the common stereotype of a "skid-row" denizen but is more often a blue- or white-collar worker or homemaker. The lifetime risk for alcoholism among physici ans is similar to that of the general population. Genetics of Alcoholism Several separate and distinct characteristics appear to contribute to the risk. For example, some families carry a risk for both alcoholism and drug dependence associated with the characteristic of high levels of impulsivity, as can be seen in the antisocial personality disorder. In other families, the risk for both al cohol and drug dependence may relate to a genetic vulnerability to schizophrenia , panic disorder, or manic depressive disease. A third and different mechanism i ncreases only the alcoholism risk (e.g., in some offspring of alcoholics and Nat ive Americans) through a low response to alcohol and subsequent drinking higher doses to achieve the desired effects. The relatively low response to alcohol con tributes to attitudes and drinking patterns that increase the risk for alcohol-r elated problems and alcoholism. By contrast, a decreased risk for heavy drinking can result from a more intense response to alcohol, as seen in approximately ha lf of Asian men and women. This is due primarily to a mutation that causes the p roduction of an inactive form of the enzyme ALDH, which results in higher levels of acetaldehyde following alcohol ingestion. Natural History Although the age of the first drink is similar in alcoholics and nonalcoholics, earlier onset of regular drinking and drunkenness is associated with a higher ri sk for later problems. By the early to mid-twenties, most nonalcoholic men and w omen moderate their drinking (perhaps learning from minor problems), whereas alc oholics are likely to escalate their patterns of drinking despite difficulties. The first major life problem from alcohol often appears in the early to mid-twen ties. Once established, the course of alcoholism is likely to be one of exacerba tions and remissions. As a rule, there is little difficulty in stopping alcohol use when problems develop, and this step is often followed by days to months of abstinence and then a period of carefully controlled drinking. Unless abstinence is maintained, however, these phases almost inevitably give way to escalations in alcohol intake and subsequent problems. The course is not hopeless; following treatment, between half and two-thirds of alcoholics maintain abstinence for ye ars, and often permanently. Even without formal treatment or self-help groups th

ere is at least a 20% chance of spontaneous remission with long-term abstinence. However, should the alcoholic continue to drink, the life span is shortened by 10 15 years on average, with the leading causes of death, in decreasing order, the result of heart disease, cancer, accidents, and suicide. Identification of the Alcoholic and Intervention Even in affluent areas ~20% of patients have an alcohol use disorder. It is impo rtant to pay attention to the alcohol-related symptoms and signs as well as labo ratory tests that are likely to be abnormal in the context of regular consumptio n of six to eight or more drinks per day. The two blood tests with 70% sensitivi ty and specificity for heavy alcohol consumption are -glutamyl transferase (GGT) (>35 U) and carbohydrate-deficient transferrin (CDT) (>20 U/L); the combination of the two is likely to be more accurate than either alone. Physicians should c onsider using these tests to screen all patients as indicators of possible alcoh olism. These serologic markers of heavy drinking can also be useful in monitorin g abstinence, as they are likely to return toward normal within several weeks of the cessation of drinking; thus, increases in values of as little as 10% are li kely to indicate a resumption of heavy alcohol intake. Other blood tests that ca n be useful in identifying individuals consuming six or more standard drinks per day include high-normal MCVs (91 m3) and serum uric acid (>416 mol/L, or 7 mg/d L). Physical signs and symptoms that can be useful in identifying alcoholism inc lude mild and fluctuating hypertension, repeated infections such as pneumonia, a nd otherwise unexplained cardiac arrhythmias. Other disorders suggestive of depe ndence include cancer of the head and neck, esophagus, or stomach as well as cir rhosis, unexplained hepatitis, pancreatitis, bilateral parotid gland swelling, a nd peripheral neuropathy. The clinical diagnosis of alcohol abuse or dependence ultimately rests on the do cumentation of a pattern of repeated difficulties associated with alcohol use; t he definition is not based on the quantity and frequency of alcohol consumption. Thus, in screening it is important to probe for life problems and then attempt to tie in use of alcohol or another substance. Information regarding marital or job problems, legal difficulties, histories of accidents, medical problems, evid ence of tolerance, etc., are important. While all physicians should be able to t ake the time needed to gather such information, some standardized questionnaires can be helpful, including the 10-item Alcohol Use Disorder Screening Test (AUDI T) (Table 387-2). However, these are only screening tools, and a careful face-to -face interview is still required for a meaningful diagnosis. Table 387-2 The Alcohol Use Disorders Identification Test (Audit)a

Item 5-Point Scale (Least to Most) 1. How often do you have a drink containing alcohol? Never (0) to 4+ per week (4 ) 2. How many drinks containing alcohol do you have on a typical day? 1 or 2 (0) t o 10+ (4) 3. How often do you have six or more drinks on one occasion? Never (0) to daily or almost daily (4) 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never (0) to daily or almost daily (4) 5. How often during the last year have you failed to do what was normally expect ed from you because of drinking? Never (0) to daily or almost daily (4) 6. How often during the last year have you needed a first drink in the morning t o get yourself going after a heavy drinking session? Never (0) to daily or almos t daily (4) 7. How often during the last year have you had a feeling of guilt or remorse aft er drinking? Never (0) to daily or almost daily (4)

8. How often during the last year have you been unable to remember what happened the night before because you had been drinking? Never (0) to daily or almost da ily (4) 9. Have you or someone else been injured as a result of your drinking? No (0) to yes, during the last year (4) 10. Has a relative, friend, doctor or other health worker been concerned about y our drinking or suggested that you should cut down? No (0) to yes, during the la st year (4)

aThe AUDIT is scored by simply summing the values associated with the endorsed r esponse. Source: Adapted from DF Reinert, GP Allen: Alcoholism: Clinical & Experimental R esearch 26:272, 2002, and from MA Schuckit, 2006. After alcoholism is identified, the diagnosis must be shared with the patient as part of an intervention. The presenting complaint can be used as an entre to the alcohol problem. For instance, the patient with insomnia or hypertension can be told that these are clinically important problems which, in conjunction with ot her physical findings and laboratory tests, indicate that alcohol is increasing the risk for further medical and psychological problems. The physician should sh are information about the course of alcoholism and explore possible avenues of a ddressing the problem. This process can be carried out by any physician or other health care provider. Several protocols, categorized as brief interventions and motivational interviewing, are available for health care workers to follow. The technique of brief interventions has been shown to be effective in decreasing a lcohol use and problems when instituted as two 15-min sessions 1 month apart, al ong with a telephone follow-up reminder. Motivational interviewing uses the clin ician's level of concern and understanding of the need for patients to progress through their own stages of enhanced understanding of their problems to optimize their ability to alter their drinking behaviors. The process of intervention is rarely accomplished in one session. Multiple sess ions to explain the problem, the optimal treatments, and the benefits of making certain lifestyle changes are often required. For the person who refuses to stop drinking at the first intervention, a logical step is to "keep the door open," establishing future meetings so that help is available as problems escalate. In the meantime the family may benefit from counseling or referral to self-help gro ups such as Al-Anon (the Alcoholics Anonymous group for family members) and Alat een (for teenage children of alcoholics). The Alcohol Withdrawal Syndrome Once the brain has been repeatedly exposed to high doses of alcohol, any sudden decrease in intake can produce withdrawal symptoms, many of which are the opposi te of those produced by intoxication. Features include tremor of the hands (shak es or jitters); agitation and anxiety; autonomic nervous system overactivity inc luding an increase in pulse, respiratory rate, and body temperature; and insomni a, sometimes accompanied by frightening dreams. Because alcohol has a short half -life, these withdrawal symptoms generally begin within 5 10 h of decreasing ethan ol intake, peak in intensity on day 2 or 3, and improve by day 4 or 5. Anxiety, insomnia, and mild levels of autonomic dysfunction may persist to some degree fo r 4 6 months as a protracted abstinence syndrome, which may contribute to the tend ency to return to drinking. At some point in their lives, between 2 and 5% of alcoholics experience withdraw al seizures, often within 48 h of stopping drinking. These rare events usually i

nvolve a single generalized seizure, and electroencephalographic abnormalities g enerally return to normal within several days. The term delirium tremens (DTs) refers to an uncommon state of intense acute wit hdrawal that includes delirium (mental confusion, agitation, and fluctuating lev els of consciousness) associated with a tremor and autonomic overactivity (e.g., marked increases in pulse, blood pressure, and respirations). Fortunately, this serious and potentially life-threatening complication of alcohol withdrawal is seen in <5% of alcohol-dependent individuals; the chance of DTs during any singl e withdrawal is <1%. DTs are most likely to develop in patients with concomitant severe medical disorders and can usually be avoided by identifying and treating the underlying medical conditions. Alcohol-Related Conditions: Treatment Acute Intoxication The first priority is to assess vital signs and manage respiratory depression, c ardiac arrhythmia, or blood pressure instability, if present. The possibility of intoxication with other drugs should be considered, and blood and urine samples are obtained to screen for opioids or other CNS depressants such as benzodiazep ines or barbiturates. Other medical conditions that must be considered include h ypoglycemia, hepatic failure, or diabetic ketoacidosis. Patients who are medically stable should be placed in a quiet environment. If re cumbent, patients should lie on their side to minimize the risk of aspiration. W hen the intoxicated person is aggressive or violent, hospital procedures should be followed, including planning for the possibility of a show of force with an i ntervention team. In the context of aggressiveness, patients should be reminded in a clear and nonthreatening way that the staff wants to help them to feel bett er and to avoid problems. If the aggressive behavior continues, relatively low d oses of a short-acting benzodiazepine such as lorazepam (e.g., 1 2 mg PO or IV) ma y be used and can be repeated as needed, but care must be taken so that the addi tion of this second CNS depressant does not destabilize vital signs or worsen co nfusion. An alternative approach is to use an antipsychotic medication (e.g., 0. 5 5 mg of haloperidol PO or IM every 48 h if needed), but this has the potential d anger of lowering the seizure threshold. Two other medications useful for agitat ion are ziprasidone (10 mg IM every 2h as needed, up to 40 mg) and olanzapine (2 .5 10 mg IM repeated at 2 h and 6 h, if needed). If aggression escalates, the pati ent might require a short-term admission to a locked ward, where medications can be used more safely and vital signs more closely monitored. Withdrawal The first step is to perform a thorough physical examination in all alcoholics w ho are considering stopping drinking, including a search for evidence of liver f ailure, gastrointestinal bleeding, cardiac arrhythmia, infection, and glucose or electrolyte imbalance. The second step is to offer reassurance that the acute withdrawal is short lived and to offer adequate nutrition and rest. All patients should be given oral mul tiple B vitamins, including 50 100 mg of thiamine daily for a week or more. Becaus e most alcoholics who enter withdrawal are either normally hydrated or mildly ov erhydrated, IV fluids should be avoided unless there is evidence of significant recent bleeding, vomiting, or diarrhea. Medications can usually be administered orally. The third step in treatment is to recognize that most withdrawal symptoms are ca used by the rapid removal of a CNS depressant, in this case, alcohol. The sympto ms can be controlled by administering any drug of this class in doses that decre

ase the agitation, and gradually taper the dose over 3 5 days. While most CNS depr essants are effective, benzodiazepines (Chap. 386) have the highest margin of sa fety and lowest cost and are, therefore, the preferred class of drugs. Benzodiaz epines with short half-lives are especially useful for patients with serious liv er impairment or evidence of preexisting encephalopathy or brain damage. However , short-acting benzodiazepines such as lorazepam can produce rapidly changing dr ug blood levels and must be given every 4 h to avoid abrupt fluctuations that ma y increase the risk for seizures. Therefore, most clinicians use drugs with long er half-lives, such as diazepam or chlordiazepoxide, administering enough drug o n day 1 to alleviate most of the symptoms of withdrawal (e.g., the tremor and el evated pulse) and then gradually decreasing the dose over a period of 3 5 days. Th e approach is flexible; the dose is increased if signs of withdrawal escalate, a nd the medication is withheld if the patient is sleeping or shows signs of incre asing orthostatic hypotension. The average patient requires 25 50 mg of chlordiaze poxide or 10 mg of diazepam given PO every 4 6 h on the first day. Treatment of the patient with DTs can be challenging, and the condition is likel y to run a course of 3 5 days regardless of the therapy employed. The focus of car e is to identify and correct medical problems and to control behavior and preven t injuries. Many clinicians recommend the use of high doses of a benzodiazepine (as much as 800 mg/d of chlordiazepoxide has been reported), a treatment that wi ll decrease agitation and raise the seizure threshold but probably does little t o improve the confusion. Other clinicians recommend the use of antipsychotic med ications, such as haloperidol, ziprasidone, or olanzapine as discussed above, al though these drugs have not been directly evaluated for DTs. Antipsychotics are less likely to exacerbate confusion but may increase the risk of seizures; they have no place in the treatment of mild withdrawal symptoms. Generalized withdrawal seizures rarely require aggressive pharmacologic interven tion beyond that given to the usual patient undergoing withdrawal, i.e., adequat e doses of benzodiazepines. There is little evidence that anticonvulsants such a s phenytoin or gabapentin are effective in drug-withdrawal seizures, and the ris k of seizures has usually passed by the time effective drug levels are reached. The rare patient with status epilepticus must be treated aggressively (Chap. 363 ). While alcohol withdrawal is often treated in a hospital, efforts at reducing cos ts have resulted in the development of outpatient detoxification for relatively mild abstinence syndromes. This is appropriate for patients in good physical con dition who demonstrate mild signs of withdrawal despite low blood alcohol concen trations and for those without prior history of DTs or withdrawal seizures. Such individuals still require a careful physical examination, appropriate blood tes ts, and vitamin supplementation. Benzodiazepines can be given in a 1- to 2-day s upply to be administered to the patient by a spouse or other family member four times a day. Patients are asked to return daily for evaluation of vital signs an d to come to the emergency room if signs and symptoms of withdrawal escalate. Rehabilitation of Alcoholics After completing alcoholic rehabilitation, 60% of alcoholics, especially middle class patients, maintain abstinence for at least a year, and many achieve lifeti me sobriety. The core of treatment begins with helping patients recognize the need to change, while working with them to alter their behaviors to enhance compliance. Therape utic maneuvers fall into several general categories, which are applied to all pa tients regardless of age or ethnic group. The manner in which the treatments are used should be sensitive to the practices and needs of specific populations. Th e first step is to help the alcoholic achieve and maintain a high level of motiv ation toward abstinence. This includes education about alcoholism and instructio

ns to family and/or friends to stop protecting the patient from problems caused by alcohol. The second step is to help the patient readjust to life without alco hol and to reestablish a functional lifestyle through counseling, vocational reh abilitation, and self-help groups such as Alcoholics Anonymous (AA). The third c omponent, called relapse prevention, helps the patient to identify situations in which a return to drinking is likely, formulate ways of managing these risks, a nd develop coping strategies that increase the chances of a return to abstinence if a slip occurs. For many patients, especially those who are highly motivated and have supportive social systems, treatment can be on an outpatient basis. However, more intense interventions work better than less intensive measures, and some alcoholics do n ot respond to outpatient approaches. The decision to hospitalize or utilize resi dential care can be made if (1) the patient has medical problems that are diffic ult to treat outside a hospital; (2) depression, confusion, or psychosis interfe res with outpatient care; (3) there is a severe life crisis that makes it diffic ult to work in an outpatient setting; (4) outpatient treatment has failed; or (5 ) the patient lives too far from the treatment center to participate in an outpa tient program. The best predictors of continued abstinence include evidence of h igher levels of life stability (e.g., supportive family and friends) and higher levels of functioning (e.g., job skills, higher levels of education, and absence of crimes unrelated to alcohol). Whether the treatment begins in an inpatient or an outpatient setting, subsequen t outpatient contact should be maintained for a minimum of 6 months and preferab ly a full year after abstinence is achieved. Counseling with an individual physi cian or through groups focuses on day-to-day living, emphasizing areas of improv ed functioning in the absence of alcohol (i.e., why it is a good idea to continu e to abstain) and helping the patient to manage free time without alcohol, devel op a nondrinking peer group, and handle stresses on the job. The physician serves an important role in identifying the alcoholic, diagnosing and treating associated medical or psychiatric syndromes, overseeing detoxificat ion, referring the patient to rehabilitation programs, and providing counseling. Physicians are also responsible for selecting which (if any) medication might b e appropriate during alcoholism rehabilitation. Patients often complain of conti nuing sleep problems or anxiety when acute withdrawal treatment is over, problem s that may be a component of protracted withdrawal. In general, hypnotics or ant ianxiety drugs should be avoided in this situation. Patients should be reassured that the trouble sleeping is normal after alcohol withdrawal and will improve o ver the subsequent weeks and months. Patients should follow a rigid bedtime and awakening schedule and avoid naps or the use of caffeine in the evenings. The sl eep pattern will improve with time, and the patient can avoid the rebound insomn ia associated with most hypnotics and the risk for developing dependence on anot her depressant. Anxiety can be addressed by helping the person to gain insight i nto the temporary nature of the symptoms and to develop strategies to achieve re laxation as well as by using forms of cognitive therapy. While the mainstay of alcoholic rehabilitation involves counseling, education, a nd cognitive approaches, several medications might be useful. The optimal length of time to continue these drugs in the context of a positive response is unclea r, but most clinicians would recommend 6 12 months. The first is the opioid-antago nist drug naltrexone, 50 150 mg/d, which has been reported to decrease the probabi lity of a return to drinking and to shorten periods of relapse. Recently a onceper-month injection of this drug (380 mg) has been developed to help improve com pliance. By blocking opioid receptors, naltrexone may decrease activity in the d opamine-rich ventral tegmental reward system, or decrease the feeling of pleasur e or reward if alcohol is imbibed. The improved rate of functioning and abstinen ce with this drug is modest. The side effects are relatively few at the recommen ded doses and include gastrointestinal distress. A second medication, acamprosat

e (Campral), 2 g/d, has been widely tested in patients in the United States and Europe; results are generally similar to those reported for naltrexone. This dru g inhibits the actions of NMDA receptors and has been hypothesized to act by dec reasing mild symptoms of protracted withdrawal. There are few side effects, asid e from mild gastrointestinal distress. Several long-term trials of combined nalt rexone and acamprosate using doses similar to those noted above have reported th at the combination may be superior to either drug alone, although not all studie s agree. Disulfiram, an ALDH inhibitor, has been used extensively in the past for treatme nt of alcoholism. In doses of 250 mg/d this drug produces an unpleasant (and pot entially dangerous) reaction in the presence of alcohol, a phenomenon related to rapidly rising blood levels of the first metabolite of alcohol, acetaldehyde. F ew adequate controlled trials have demonstrated a clear superiority of disulfira m over placebo. Drinking alcohol while taking disulfiram produces a reaction inv olving an increased pulse, changes in blood pressure, and vomiting and diarrhea. This can be dangerous, especially for patients with heart disease, stroke, diab etes mellitus, or hypertension. The drug itself has also been reported to carry potential risks of depression, psychotic symptoms, peripheral neuropathy, and li ver damage. Thus, most clinicians reserve this medication for patients who have a clear history of longer-term abstinence associated with prior use of disulfira m, and for those who might take the drug under the supervision of another indivi dual (such as a spouse), especially during discrete periods identified as repres enting high-risk drinking situations for them (such as the Christmas holiday). O ther drugs under investigation for possible use in alcoholism rehabilitation inc lude the serotonin antagonist ondansetron; topiramate, an anticonvulsant with po ssible effects on dopamine; and the cannabinol receptor antagonist ramonibant; a t present, there are insufficient data to support their use in clinical settings . Additional support for alcoholics and their relatives and friends is available t hrough self-help programs such as AA. These groups, which typically consist of r ecovering alcoholics, offer an effective model of abstinence, provide a sober pe er group, and make crisis intervention freely available when the urge to drink e scalates. This can help patients optimize their chances for recovery, especially when incorporated into a more structured treatment milieu. Further Readings Babor TF et al: Brief interventions for at-risk drinking: Patient outcomes and c ost-effectiveness in managed care organizations. Alcohol 41:624, 2006 [PMID: 170 35245] Gelernter J et al: Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and r esponse to naltrexone treatment for alcohol dependence: Results from the VA Coop erative Study. Alcohol Clin Exp Res 31:555, 2007 [PMID: 17374034] Lawrence AJ: Therapeutics for alcoholism: What's the future? Drug Alcohol Rev 26 :3, 2007 [PMID: 17364830]

Bibliography Anton RF et al: Combined pharmacotherapies and behavioral interventions for alco hol dependence: The COMBINE Study: A randomized controlled trial. JAMA 295:2003, 2006 [PMID: 16670409]

Dick DM et al: Marital status, alcohol dependence, and GABRA2: Evidence for gene -environment correlation and interaction. J Stud Alcohol 67:185, 2006 [PMID: 165 62401] Gomez A et al: A diagnostic usefulness of brief versions of Alcohol Use Disorder s Identification Test (AUDIT) for detecting hazardous drinkers in primary care s ettings. J Stud Alcohol 66:305, 2005 [PMID: 15957683] Kung F et al: Cost-effectiveness analysis of a brief intervention delivered to p roblem drinkers presenting at an inner-city hospital emergency department. J Stu d Alcohol 65:363, 2004 Miller WR et al: Addressing substance abuse in health care settings. Alcohol Cli n Exp Res 30:292, 2006 [PMID: 16441278] Mundt M et al: Brief physician advice for problem drinking among older adults: A n economic analysis of costs and benefits. J Stud Alcohol 66:389, 2005 [PMID: 16 047528] Schuckit MA: Drug and Alcohol Abuse: A Clinical Guide to Diagnosis and Treatment , 6th ed. New York, Springer, 2006 : An overview of genetic influences in alcoholism. Alcohol Clin Exp Res, in press , Smith TL: An evaluation of the level of response to alcohol, externalizing sympto ms, and depressive symptoms as predictors of alcoholism. J Stud Alcohol 67:215, 2006 Toumbourou JW et al: Youth alcohol and other drug use in the United States and A ustralia: A cross-national comparison of three state-wide samples. Drug Alcohol Rev 24:515, 2005 [PMID: 16361208]

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