Etiology

Liability to alcohol abuse and dependence, especially early-onset abuse, runs in families, but the mechanism of inheritance is not understood. Findings of a link between alcoholism and a particular dopamine DR-2 receptor allele remain controversial. Some Asian populations are relatively protected from alcoholism because they possess a variant form of the enzyme alcohol dehydrogenase and metabolize alcohol poorly. This causes them to become flushed and nauseated with minimal doses. Conversely, young adults with a high alcohol tolerance, evaluated on measures of incoordination or subjectively, are at increased risk for later alcoholism. Young adults often assume they are not getting into difficulties with drinking because of their tolerance. Physicians must convince them that this is wrong.

Alcohol is a central nervous system (CNS) depressant with cross-tolerance to benzodiazepines, barbiturates, and some other sedatives. It is distinguished within this group by its ease of manufacture, legal status, wide availability, rapid absorption, and exceptionally low therapeutic index. The lethal dose of alcohol is only a few times the intoxicating dose; one bottle of whiskey can be lethal to an individual who has not acquired tolerance. The dose at which tissue damage occurs is lower in this setting and falls within the range of commonly ingested doses. In most adults, chemical signs of hepatic injury are detectable after consumption of three or more drinks within 24 hours. Alcohol is a potent fetal teratogen with no threshold dose; it is absolutely contraindicated in pregnancy.

Clinical Presentation

Acute alcohol intoxication at moderate doses causes disinhibition and incoordination. Even at socially acceptable doses, it impairs driving and is implicated in approximately half of all highway accidents and deaths. Alcohol is linked to a similar proportion of sexual assaults.

Patients with most major psychiatric illnesses have increased rates of alcohol abuse. Alcohol interacts with psychiatric illnesses and treatments. Many patients use alcohol to treat mood disorders, anxiety, or insomnia, but it is not a safe or effective treatment for any medical disorder. The toxicity and short duration of action of alcohol make it useless as an anxiolytic, and it disrupts sleep architecture and decreases sleep efficiency. The combination of alcohol abuse and depression is especially lethal. Alcohol use makes patients who are depressed more depressed and interferes with antidepressant response. Drinkers who are depressed experience an approximately 10-fold increase in suicide rate compared with nondrinkers who are depressed.

Alcohol has direct toxic effects on multiple tissues, including the central nervous system, liver, the pancreas, and the heart. Patients may present with acute or chronic hepatitis, cirrhosis, esophageal varices, cardiomyopathy, and dementia. Acute withdrawal syndromes occur occasionally, leading to delirium tremens, Wernicke encephalopathy, and Korsakoff psychosis, as illustrated in Chapter 17.

Wernicke syndrome, an acute neurologic emergency resulting from acute thiamine and other B-vitamin depletion, is seen almost exclusively in alcoholics. It is initially manifested by gait ataxia, and subsequently oculomotor abnormalities and delirium, developing during a period of days to weeks and presents with confusion, ophthalmoplegia with diplopia and nystagmus, and ataxia. The delirium is characterized by disorientation, inattention, drowsiness, and indifference to surroundings. Conversation is sparse and tangential. Signs of alcohol withdrawal are seen in 15% of patients. Treatment of Wernicke syndrome requires immediate administration of large doses of thiamine, 100 mg intravenous (IV) in a non–glucose containing solution. This reverses the symptoms and prevents progression of pathology. This treatment is routinely provided in emergency departments for most patients presenting with an acute confusional state. Progressive stupor, coma, and death develop if the condition is left untreated. Thiamine and other B vitamins should be given to malnourished patients as supplements to replenish body stores.

Autopsy reveals symmetric necrosis of brainstem tegmentum nuclei, superior cerebellar vermis, and mammillary bodies. These findings resemble lesions produced by disorders of pyruvate metabolism.

Korsakoff psychosis is likely to develop without immediate repletion of thiamine in Wernicke syndrome patients. This disorder is mostly confined to alcoholics, with the only exception being individuals having bilateral hippocampal damage, typically from vertebral basilar infarction. This condition is a nonprogressive devastating irretrievable disorder of memory, affecting both new learning (anterograde amnesia) and past memory (retrograde amnesia). The patient cannot make new memories because of poor encoding, which is similar to the memory impairment of Alzheimer disease. The retrograde amnesia may extend back many years, rendering the patient “stuck in time.” Recollection of past events is usually disorganized and erratic, sometimes suggesting deliberate confabulation. Additional cognitive impairment includes poor sequencing, arithmetic, and construction performance.

Hepatic encephalopathy occurs in stages. Patients with liver failure experience confusion, with decreased psychomotor activity associated with increasing serum levels of NH₃. Occasionally, hyperactivity and agitation occur. During this time, patients often exhibit asterixis, which is not a sign specific to hepatic encephalopathy because it can occur in many other metabolic disturbances, such as uremic encephalopathy. Progressive stages of drowsiness, stupor, and coma follow. Significant motor abnormality develops, including rigidity, bradykinesia, brisk reflexes, and extensor plantar reflexes. Seizures may occur.

The progression of symptoms varies considerably, particularly after treatment begins. However, left untreated, coma may persist and lead to death in up to 50% of patients. In some cases, a chronic disorder of cognition and behavior occurs, with pyramidal and extrapyramidal dysfunction lasting months or years. This condition is seen in patients with repetitive bouts of hepatic encephalopathy. EEG shows generalized slowing of background rhythm with prominent triphasic waves. The purpose of treatment is to attempt to decrease NH₃ levels by reducing dietary protein, acidifying colonic contents with lactulose, and, occasionally, suppressing urease-producing colonic bacteria with antibiotics.

Diagnosis

To avoid missing the diagnosis of alcohol abuse or dependence, physicians must maintain a high index of suspicion directed at eliciting classic historic signs of impending alcohol abuse (Fig. 20-2). Similarly, asking about features suggestive of early alcohol dependence is equally important during what needs to be routine screening for alcoholism in any patient (Fig. 20-3). Asking about average levels and patterns of alcohol use should be part of every examination. Because patients underestimate their consumption, a useful rule of thumb is to double the amount reported by the patient. Patients also need to be questioned about binge drinking, withdrawal signs, blackouts, and excessive tolerance. The four-question CAGE questionnaire is a good screening instrument (Box 20-1). One positive answer to a CAGE question is cause for concern; two positive answers corresponds to a 50% risk of alcoholism.

Figure 20-3 Alcohol Dependence.

Any individual who has had even one driving while intoxicated (DWI) drunk-driving conviction can be safely assumed to have a problem with alcohol, as can the occasional patient who presents in an intoxicated state for his appointment. In the latter case, the physician must take whatever steps are immediately necessary to prevent this patient from driving away from the medical office.

When diagnostic uncertainty persists, interviewing family or friends is often decisive; typically, they present a more accurate picture of the patient’s drinking habits. Laboratory test results that reveal increased GGTP or transaminase levels, mild macrocytic anemia, or both can add confirmatory evidence. Asking the patient to stop drinking for 6 months is helpful as both a diagnostic and a therapeutic maneuver. Heavy drinkers who achieve a few months of sobriety may feel so much better that they stay sober, and patients who refuse clearly have very serious trouble.

Treatment

Withdrawal from alcohol and other cross-tolerant sedative hypnotics (barbiturates, benzodiazepines, methaqualone, etc.) is potentially hazardous (Figs. 20-4 to 20-6). This can lead to agitated delirium and seizures. In contrast, most other pharmacologic withdrawals are characterized by dysphoria but are not medically dangerous; nevertheless, withdrawal from cocaine and amphetamines can lead to a profound depression.

Figure 20-4 Alcohol Withdrawal.

Figure 20-5 Opioid Withdrawal.

Figure 20-6 Benzodiazepine Withdrawal.

Addicted patients must remove themselves from environments wherein these drugs are available and their use is encouraged or tolerated. Twelve-Step organizations like Alcoholics Anonymous and other self-help groups are extremely valuable in overcoming denial of illness and in providing patients a culture of sobriety and social support. The absolute treatment goal is total current and future abstinence. Although therapies incorporating a return to controlled use have been repeatedly proposed, these approaches are always unsuccessful.

Pharmacologic treatments for addiction are improving but are still adjunctive to psychotherapeutic and behavioral interventions. Long-term replacement of illicit opiates with methadone or buprenorphine is effective, as is the temporary use of nicotine administered by patch, gum, or inhalation to help smokers quit. The use of bupropion modestly increases the success rate of quitting cigarettes. Varenicline, a nicotine receptor partial agonist, works even better, but possibly at the cost of precipitating mood disturbances.

Disulfiram (Antabuse) is the oldest specific medicine to be prescribed to prevent use of alcohol. Unexpectedly, disulfiram also has been found to have some utility for therapy of cocaine abuse. By inhibiting a critical hepatic enzyme in the metabolic degradation of alcohol, disulfiram induces an unpleasant and potentially dangerous reaction to this therapy, whenever the reforming addict returns to alcohol ingestion. Disulfiram works best in highly motivated but intermittently impulsive binge drinkers. However, this therapeutic approach is not only potentially hazardous but totally dependent on patient motivation. It is easy for an alcoholic to simply choose to stop using the medicine.

Two other medications are approved for the treatment of alcoholism: Naltrexone is an opiate antagonist that also reduces alcohol intake, presumably by diminishing the rewarding effects of alcohol. Acamprosate is thought to subtly diminish protracted withdrawal systems by modulating glutamatergic activity. To date, there are no accepted pharmacologic treatments for cocaine and other types of stimulant dependence. The most promising agents (topiramate, vigabatrin, etc.) increase GABA activity. Cocaine vaccines are also under investigation.

Liability to alcoholism, especially early-onset alcoholism, is partially inherited, as may be the case with other addictions. Physiologic and epidemiologic evidence suggest that the adolescent brain is especially vulnerable to addiction, particularly to nicotine; few smoking habits begin after age 18. Persons with psychiatric illnesses, especially bipolar disorder, ADHD, and personality disorders, are at heightened risk for drug abuse and dependence. ADHD is diagnosable by age 8 and never starts in adulthood.

Some psychiatrists believe that many addicts are in fact “self-medicating” an underlying psychiatric disorder—this idea remains controversial. However, “dual diagnosis” patients are the rule rather than the exception. These individuals need simultaneous treatment for both addiction and psychiatric illness.