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13 HEALTH CONSEQUENCES OF ALCOHOL ABUSE: OPPORTUNl'llE;S FOR TREATMENT RESEARCH Alcohol abuse has diverse deleterious effects on health including intoxication, the withdrawal syndrome, and many types of organ damage. The advances in our understanding of how alcohol-related organ damage occurs were reviewed in the IOM report Causes and Consequences of Alcohol Problems (IOM, 1987~. This chapter focuses on opportunities for treatment research on alcohol-related illnesses. In terms of mortality, hepatic cirrhosis is probably the most serious alcohol-related disease. In terms of handicapped daily functioning, however, the cognitive impairment induced by alcohol abuse may be more serious. Although advances have been made in treating some alcohol-related illnesses, other disorders have no specific treatment. In general, in the prevention and containment of alcohol-related organ pathology, the paramount concern is to halt the patient's alcohol abuse because abstinence from alcohol in these cases is essential to allow reversibility of organ damage (where possible) and to prevent the progression of cellular and tissue damage. In considering research approaches to the treatment of alcohol-related health consequences, multisite studies are essential in cases in which the illness occurs with such low frequency that no single site can provide a sufficient number of subjects. Alcoholic hallucinosis, panaeatitis, cardiomyopathy, and certain consequences of cirrhosis of the liver are examples of such disorders. On the other hand, controlled treatment trials for detoxification or for cognitive impairment could be carried out at either single or multiple sites. INTOXICATION Work on amethystic agents (agents that reverse intoxication) is in the basic research stage and is not yet ready for treatment evaluation or treatment applications. Liskow and Goodwin (1987) have reported that no single drug reverses all the effects of alcohol. Naloxone reverses the depression of the ventilators response to hypercapnia that is induced by alcohol, but it does not help as a sobering agent. Lithium may attenuate the subjective sense of intoxication. Zimelidine and ibuprofen appear to reduce several types of alcohol-induced cognitive impairment. None of these effects appears to be pronounced, however, and none of these compounds would qualify as an amethystic agent. Basic research on the effects of alcohol on membrane proteins, especially the calcium and chloride channels, may lead to the development of new drugs that could block the intoxicating effects of alcohol. Because alcohol intoxication is associated with a wide variety of central nervous system effects including anxiolysis, psychomotor depression, problems of coordination and gait, cognitive impairment, and changes in mood and behavior related to environmental contexts, studies of amethystic agents will have to specify the particular effects of alcohol that are reversed or blocked by the drug. At the present time, certain calcium channel blockers and drugs that serve as partial inverse agonists at the benzodiazepine/GABA chloride channel complex offer promising opportunities for future research on amethystic agents. However, this work is not yet ready for formal study in a -267

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treatment research paradigm on the reversal of alcohol intoxication. ALCOHOL WITHDRAWAL Pharmacotherapies for Alcohol Withdrawal A large number of studies, beginning with the work of Kaim, Klett, and Rothfeld (1969), have demonstrated the superiority and safety of benzodiazepines over other drugs (e.g., chlorpromazine and hydroxyzine) in the treatment of alcohol withdrawal. Later studies expanded on this work by evaluating a range of benzodiazepines and concluded that all are efficacious for alcohol withdrawal (Liskow and Goodwin, 1987~. The clear establishment of the efficacy of benzodiazepines for alcohol detoxification is a major research accomplishment that emerges from studies conducted during the past 20 years (Moskowitz et al., 1983~. Sellers and coworkers (1983) have exploited diazepam's long duration of action in developing what they call the loading benzodiazepine dose technique. In this method, a 20-milligram (mg) oral dose of diazepam is given at intervals of 1 to 2 hours until clinical improvement occurs or until the patient becomes sedated. In one recent study, all patients treated using this technique successfully completed detoxification, and 50 percent responded within 7.6 hours to an oral dose of 60 mg of diazepam. Only an occasional patient required treatment for more than 24 hours. No patients had serious withdrawal reactions such as seizures, hallucinations, or arrhythmias (Sellers et al., 1983~. Several other nonbenzodiazepine agents have been evaluated, and all seem to reduce many of the peripheral signs of alcohol withdrawal, but they should be used cautiously because they do not work as well as benzodiazepines in suppressing the more serious symptoms of alcohol withdrawal (e.g., seizures, delirium tremens) (Schuckit, 1987~. For example, beta blockers attenuate the symptoms of autonomic hyperactivity in alcohol withdrawal, but Liskow and Reed (1986) caution that this effect might disguise the warning signs of more severe symptoms, and they recommend the simultaneous prescription of benzodiazepines. Trials of alpha-2 adrenergic agonists such as lofexidine and clonidine have shown reductions in alcohol withdrawal symptom scores with both agents. However, as with the beta blockers, neither anticonvulsant effects nor the ability to suppress other severe alcohol withdrawal symptoms has been demonstrated with alpha-2 agonists (Schuckit, 1987~. Calcium channel blockers have also been tried. One study compared meprobamate with caroverine (not available in the United States) and found that both helped and were equally efficacious (Koppi et al., 1987~. A second study found that several calcium channel blockers reduced seizures and mortality in alcohol-dependent rats (Little, Dolin, and Halsey, 1986~. Few human studies have been conducted, but the limited data available suggest that this class of drugs may suppress some of the symptoms of alcohol withdrawal. One problem in using these drugs in a clinical situation is that there is a delay in the time of onset of their action; thus, they must be given several days before alcohol detoxification begins. In summary, the evidence supports the superiority of benzodiazepines over all other agents used for alcohol withdrawal based on a combination of eff'cacy, safety, and rapidity of onset. The research agenda for pharmacotherapy of alcohol withdrawal will probably be better served by a shift away from studies of which drug class works best and toward the following issues: how to determine when pharmacotherapy is indicated, how to use it most -268

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e~ectiveh,r, whether some treatment settings (e.g., inpatient versus outpatient) are better for detoxification than others, which type and dose of benzadiazepines should be used in specific situations, whether there is any advantage to combining other drugs (such as anticonvulsants) with benzodiazepines, whether to use adjunct~ve drugs (i.e. antidepressants), and how to increase compliance with rehabilitation after detoxification. Nonpharmacological Detoxification Another area of research involves studies of detoxification with psychosocial support alone. In a study done by Whitfield and colleagues (1978), treatment was administered by college graduates with a behavioral science background who were given 8 to 12 hours of classroom training in a series of clearly specified techniques. Trainees had a probationary period of one month during which they worked with an experienced person. Special attention was given to alerting the therapists to clinical signs of severe alcohol withdrawal requiring evaluation by a physician and pharmacotherapy. All patients were given supportive intervention along with a regular diet and vitamins. Very few required hospitalization or even pharmacotherapy. The average stay in treatment was two to eight days, and only 12 percent left prematurely. A follow-up of two-thirds of the patients at two years indicated that 40 percent had either maintained sobriety or improved. Studies done in other locations have replicated Whitfield's results. One of the largest and best documented of these was the Ontario Detoxication System described by Annis and coworkers (1976), in which only 3 percent of participants needed medical referral. Withdrawal Scale A number of scales to measure alcohol withdrawal have been used in many of the studies mentioned above. One of the most commonly mentioned is the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A). This instrument is a 15-item scale that measures a range of symptoms such as tremor; nausea and vomiting; sweating; tactile, auditory, and visual disturbances; hallucinations; anxiety; agitation; thought disturbances; seizures; headache; and [rushing Elf the face (Straw et al., 1981~. The scale appears to be accurate and reliable (Sellers et al., 1983), and it could be applied on a larger scale to assess the outcome of a range of detoxification techniques that are used in clinical practice. Recently, a modified version of the CIWA-A was employed in an attempt to measure the severity of alcohol dependence more objectively and to identity patients who needed pharmacotherapy (Foy, March, and Drinkwater, 1988~. The patients studied had been admitted to a general hospital for treatment of other medical or surgical problems (e.g., pneumonia, fractures). The research found, however, that although the CIWA-A was helpful in identifying most patients who needed pharmacotherapy, continuous clinical assessment was required to supplement the initial determination based on the CIWA-~ Treatment Settings There is evidence that effective detoxification using pharmacotherapy and other medical -269

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services can be delivered in an inpatient, outpatient, or psychosocial setting. A recent study randomly assigned 164 patients with mild to moderate degrees of physical dependence on alcohol to inpatient or outpatient detoxification programs, each of which used oxazepam (Hayashida et al., 1989~. The patients selected for participation were required to have no history of recent (past 24 hours) seizures or delirium tremens and no serious medical or psychiatric problems that would require hospitalization. Of the 403 patients requesting "alcohol detour, 29 (7 percent) were excluded for these reasons. Among those who agreed to participate and were assigned to inpatient treatment, 95 percent completed detoxification, compared with 72 percent of the outpatients, a difference that was statistically significant. Of the 24 outpatients who did not complete detoxification, 7 required referral to inpatient treatment: 6 of these were unable to stop drinking in the outpatient setting, and 1 required hospitalization for acute schizophrenia. In total, 59 percent of the outpatient group and 64 percent of the inpatient group enrolled in a rehabilitation program, a difference that was not significant. All patients improved, and six-month evaluations showed similar outcomes for both groups. The cost of outpatient treatment was about one-tenth that of inpatient treatment. Other nonrandomized studies of outpatient detoxification have reported similar findings (Feldman et al., 1975; Tennant, 1979; Stinnett, 1982~. A close liaison with an inpatient rehabilitation program is necessary if such treatment is to be used. Few studies of combined programs are available. Special Patient Populations There are a large number of special patient populations that present unique problems for detoxification and are not well represented in research studies (Cushman, 1988~. The uncooperative, obstreperous alcoholic may not tolerate oral medication and often pulls out intravenous lines. Lorazepam, which is the only benzodiazepine that is absorbed well intramuscularly, may be preferable for such patients. The patient with chronic obstructive Pulmonary disease. anemia. or liver disease. or the ' ~ - rid -a ~ -, ~ , ~ ~_~ _, ~,,_ elderly alcoholic who metabolizes drugs more slowly may need lower doses of benzodiazepines. These patients may be better treated with lorazepam or oxazepam (because these drugs are merely conjugated before excretion), as opposed to chlordiazepoxide or diazepam (which have more complex metabolic pathways). There is little information available about the effect of other psychiatric problems on the severity of withdrawal symptoms or about interactions between other psychotropic drugs and benzodiazepines during withdrawal treatment. The severity of the alcohol withdrawal syndrome may be accentuated in patients with dual diagnoses if they are not given ancillary psychotropic medication. Many homeless alcoholics suffer from schizophrenia or other major mental disorders (Koegel and Burnam, 1988), and very little information is available about how best to respond to their multiple needs, including the initial step of detoxification (IOM, 1988~. Treatment of Seizures The treatment of seizures in alcoholics requires the identification of patients with seizures resulting from causes other than alcohol dependence. This group needs long-term -270

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treatment with anticonvulsants. Recently, diphenylhydantoin was proposed for use in preventing seizures that result from alcohol withdrawal, but its value is currently uncertain (Liskow and Goodwin, 1987; Simon, 1988~. There appears to be agreement that diphenylhydantoin, if used, should be given in combination with a benzodiazepine. Although clear evidence is not available, some clinicians recommend the use of diphenylhydantoin in cases with a history of withdrawal seizures. Some recent work indicates that an intravenous loading dose of phenobarbital is safe and effective in preventing withdrawal seizures (Young et al., 1987; Simon, 1988~. A recent study indicates that a kindling model may apply to alcohol withdrawal syndromes and seizures. To groups of 25 male alcoholics--one with, and the other without, withdrawal seizures--were evaluated. It was found that the number of detoxifications was an important variable in the predisposition to withdrawal seizures and that this relationship was independent of the amount or duration of alcohol intake (Brown et al., 1988~. The authors raise the troubling possibility that benzodiazepines, when used without anticonvulsants, may increase the chances for withdrawal seizures because they do not reduce limbic kindling. Treatment of Delirium Tremens Although the literature is clear that benzodiazepines reduce the severity of the alcohol withdrawal syndrome, a few patients develop delirium tremens even though they are treated with apparently adequate doses of benzodiazepines. There is probably considerable variability in blood levels, depending on a range of patient and dietary factors, as has been shown in studies of antidepressant blood levels in patients with major depressive disorders. Some of those who fail to respond to benzodiazepine treatment may be rapid metabolizers; alternatively, they may manifest impaired absorption of benzodiazepines. There may be optimum benzodiazepine blood levels that are associated with the marked suppression of withdrawal symptoms, but little information is currently available in this area. A recent report describes two representative cases from a total of ten who developed benzodiazepine-resistant delirium tremens and who responded to 4 to 6 mg of dexamethasone per day, given parenterally (Fischer et al., 1988~. Engagement in Follow-up Treatment Although there is a suggestion that treatment completion and engagement in follow-up are better with the longer, medically oriented inpatient programs, these programs are also more expensive. Some indication of these effects is seen in the study by Hayashida and coworkers (1989) in which 95 percent of those completing inpatient detoxification engaged in follow-up treatment versus 72 percent of the outpatient group. In Ontario, Annis found that dropout rates were higher under a nonmedically based detoxification system than they had been under an earlier, medically based system (Annie and Smart, 1978; Annis, 1979~. Smart and Gray (1978) studied more than 700 patients treated at five treatment programs in Ontario and also found that patients receiving medically oriented treatment were more likely to remain in the follow-up treatment. If this difference in engagement rates is characteristic of medical versus nonmedical settings, it may be due to the additional psychiatric or medical treatments that are often applied in medical settings to that proportion of alcoholics who have additional psychiatric or medical problems. -27 1

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Detoxification of Alcoholics Addicted to Other Substances Many patients who apply for alcohol treatment are also addicted to cocaine, benzodiazepines, or opiates. Little information is available on the effect of additional drug use on the course of alcoholism. The doses of benzodiazepines required for detoxification may be altered by additional drug use. Inpatient treatment may often be necessary for these patients. Diazepam may be a very poor choice for detoxification with this subgroup because of its liability to abuse, especially among those who have used opiates or who have been socialized into "street" drug use (Woody, O'Brien, and Greenstein, 1975~. Alcoholic Hallucinosis and Paranoia Few studies have been done on the treatment of alcoholic hallucinosis and paranoia, but haloperidol appears to be useful in patients with severe agitation, thought disorders, and hallucinations. Because haloperidol lowers the seizure threshold, it should be used in combination with a benzodiazepine, an anticonvulsant, or both. The following are opportunities for research on the treatment of alcohol withdrawal: Research is needed to determine whether there are advantages to combining other drugs (e.g., anticonvulsants, beta blockers, calcium channel blockers, alpha-2 adrenergic agonists) with benzodiazepines in the treatment of alcohol withdrawal. Further studies are needed to develop better criteria to identity appropriate patients for nonpharmacological detoxification in nonmedical settings. Additional research is also needed to identify criteria for assigning patients appropriately to inpatient, outpatient, or psychosocial settings for supervised detoxification. Further research is needed to study the detoxification of specific patient populations such as the elderly or those with complicated medical or psychiatric disorders. Controlled studies should be performed on the pharmacological treatment of alcoholic hallucinosis. This research is best carried out as cooperative, multisite studies. There is a need for a multicenter study of the treatment of delirium tremens to examine the relationship between benzodiazepine blood levels and treatment response. The recently reported study using dexamethasone in the treatment of benzodiazepine-resistant delirium tremens needs to be examined in other settings. There is a need to examine the relationship of detoxification setting, the use of pharmacotherapy, and the ability to engage patients in follow-up treatment and aftercare. In these studies, patients should be characterized in terms of presence or absence of psychopathology and comorbid medical disorders, as well as severity of alcohol dependence and withdrawal. Studies of the treatment of alcohol withdrawal that is complicated by other drug abuse or dependence are indicated across drug classes. This type of effort may require a multisite study. Treatment of Postwithdrawal Symptoms Alcohol withdrawal is associated with a generalized hyperexcitability of the central nervous system (Hemmingsen et al., 1988), which persists for days, weeks, or longer following -272

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detoxification (Begleiter and goriest, 1979). Clinical symptoms are usually associated with anxiety, restlessness, emotional lability, and insomnia. The duration of postwithdrawal symptoms and their relationship to patient age, amount and duration of alcohol intake, and presence of associated psychiatric or medical problems are not known. It is possible that the type, duration, and amount of pharmacotherapy or psychotherapy/social support used during detoxification can influence the duration and severity of postwithdrawal symptoms. This question needs to be examined. The following are opportunities for research on postwithdrawal symptoms: Studies should be initiated on the following topics: (a) the natural course of postwithdrawal symptoms in appropriately defined subgroups of alcoholics; (b) the efficacy of pharmacological and psychosocial treatments for postwithdrawal symptoms (e.g., see Meyer, 1986~; and (c) the relationship between postwithdrawal symptoms and treatment outcome. Insomnia in Alcoholics Effects of Alcohol on Sleep Insomnia is a common problem in alcoholics during periods of drinking and abstinence. Among both social drinkers and alcoholics, a moderate dose of alcohol initially produces sedation characterized by rapid sleep onset, decreased rapid eye movement (REM) sleep, and enhanced delta or slow-wave sleep. Later in the night, as the blood alcohol concentration declines, the sedative effects diminish, and signs of alcohol withdrawal occur. These signs of withdrawal are usually more pronounced in alcoholics than in social drinkers. They are noted on the electroencephalogram by decreased slow-wave sleep, frequent arousals, more rapid shifts of sleep stage, and increased frequency of REM sleep and REM disruptions. With continued heavy drinking, such as occurs in alcoholics, the sedative effects diminish, and increased amounts of alcohol are required to attain the original levels of sedation. Similarly, withdrawal signs become more pronounced (Yules, Freidman, and Chandler, 1966; Knowles, Laverty, and Kuechler, 1968; Gross et al., 1972, 1973; Rundell et al., 1972; Gross and Hastey, 1976~. Gross and Hastey (1976) interpreted these effects as indicating increased tolerance and physical dependence. Thus, alcoholics when drinking have disrupted sleep, especially during the second half of the night. Sleep During Acute Alcohol Withdrawal Almost all investigators have found marked increases in REM sleep time associated with alcohol withdrawal. These increases are characterized by more rapid REM sleep onset and reduced inter-REM intervals. Williams and Rundell (1981) found that the most striking characteristic of this sleep was its fragmentation. Sleep onset is usually not delayed, but it is constantly disrupted by restless bodily movement and brief arousals. These interruptions are especially prominent during REM sleep. The increases in REM time and restless sleep associated with acute alcohol withdrawal diminish rapidly, and by the sixth or eighth day after detoxification is completed, the total -273

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amount of REM time has returned to normal (Allen et al., 1971~. However, the overall pattern of sleep remains abnormal and is characterized by increases in stage 1 and decreases in stage 4 sleep. The fragmented sleep noted above continues, although to a lesser degree, and sleep is characterized by delays in onset, more rapid changes between stages, and a decrease in the total amount of sleep time. Improvement with Abstinence Several researchers have followed abstinent alcoholics over extended periods of time to see if and when these abnormalities disappear. Most have found evidence of gradual improvement over a period of years; some have found persistent disturbances (Adamson and Burdick, 1973; Wagman and Allen, 1975; Williams and Rundell, 1981; Imatoh et al., 1986~. There may be an alteration in the circadian rhythm of REM sleep in abstinent alcoholics. Most studies have found prolonged sleep disturbances, with the most severe disruptions diminishing within days to weeks after detoxification. There are no clear data on what percentage of alcoholics eventually develops normal sleep (and how long it takes) or on the causes of sleep disturbances. One might predict that alcoholics with sleep disturbances would be more likely to drop out of treatment and return to drinking earlier than those who do not have them; however, whether this trend in fact occurs is unclear because few data are available in this area. Moreover, although the kinds of sleep problems that generally occur are highly suggestive of toxic effects secondary to excessive and prolonged alcohol consumption, the studies do not exclude the possibility that some of the observed sleep problems predate the alcoholism and are contributors to its onset and maintenance. Influence of Detoxification Procedures on Sleep Disorders There is little information available about the influence of detoxification procedures on sleep disturbances. The most severe disorders are limited to the few days after detoxification, and many advise a conservative approach with only general supportive and educational measures. One study compared detoxification using low doses of alcohol versus chlordiazepoxide (CDP) and found that the CDP group experienced marked suppression of REM sleep along with virtual elimination of stage 3 and stage 4 sleep, whereas patients in the low-dose alcohol group had significantly less disruption of sleep (Funderburk, Allen, and Wagman, 1978~. All 18 subjects studied completed treatment, indicating no obvious problems while using alcohol for detoxification in a hospital setting. Long-term follow-up was not available; thus, it is uncertain if any delayed adverse effects occurred in the alcohol-treated group. This study is especially interesting because there is so little available information about the effects of detoxification procedures on such postwithdrawal symptoms as insomnia. It would be useful to examine the effect of several pharmacotherapies on sleep and also to see if there are differences in the type, severity, or prevalence of sleep disturbances in those who are detoxified with supportive care only versus those given pharmacotherapy. Similarly, studies could evaluate the efficacy of behavioral treatments, that have been shown to reduce insomnia in a substantial proportion of nonalcoholics (IOM, 1979~. -274

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The following are opportunities for research on sleep disorders: Studies could be conducted to determine if sleep disturbance predisposes individuals to alcoholism. This type of research might be possible by following the careers of people who have been treated for primary sleep disorders. Another promising route of investigation might be to determine how long sleep disturbances last in groups that differ on such important variables as age, psychopathology, years of drinking, medical status, and level of physiologic dependence. The influence of sleep disturbances on outcome after rehabilitation could be studied. Studies could be performed using pharmacotherapies and behavior therapies for postdetoxification insomnia. Types of Impairments NERVOUS SYSTEM EPPE;CrS Cognitive Impairment in Alcoholism Lee two most prominent cognitive impairments in alcoholism are alcoholic amnestic disorder (Wernicke-Korsakoff syndrome) and alcoholic dementia. Wernicke-Korsakoffs syndrome is associated with prolonged and hearty use of alcohol and often follows an acute episode of Wernicke's encephalopathy. It is characterized by clear consciousness and severe anterograde and retrograde amnesia. Memory problems are so pronounced that disorientation may occur. Confabulation, which tends to disappear over time, is often seen. Although its exact etiology is unclear, alcoholic amnestic disorder is felt to be largely preventable by proper diet and administration of vitamins, including thiamine. It is seen infrequently in current medical practice, but it generally is incurable once it has developed: 80 percent of all Korsakoff patients show no improvement and have a lifelong disability. Recently, Martin and coworkers (1989) reported some improvement in cognitive function in Korsakoff patients treated with fluvoxamine. Alcoholic dementia has a gradual onset and thus presents with varying degrees of impairment. It is characterized by difficulties in short- and long-term memory, abstract thinking, and judgment and by other disturbances of higher cortical function (e.g., apraxia, constructional difficulties--the inability to assemble blocks or arrange sticks in specific designs), and reductions in problem-solving ability. It is associated with poor performance on tests of psychomotor speed and with impaired control of impulses. Verbal I.Q. is less affected and usually remains within the normal range (Grant, 1987; see also Graff-Redford et al., 1982~. Although alcoholic dementia is a common problem, as many as 25 percent of alcoholics have no measurable cognitive deficits (Goldstein and Shelly, 1980~. Alcohol-related central nervous system pathology is discussed at greater length in Causes and Consequences of Alcohol Problems (IOM, 1987~. From the perspective of opportunities for treatment research, it is important to note that many cognitive deficits improve with abstinence, although often not completely (McCrady and Smith, 1986~. Most of the improvement occurs within the first two to three weeks, but there also appears to be a more gradual and continuing recovery with prolonged abstinence (Brands et al., 1983~. Short-term memory and psychomotor skills are usually the first to -275

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recover; visual-spatial learning, long-term memory, and abstraction are most resistant to improvement. For example, Brandt and colleagues (1983) studied cognitive loss and its recovery in long-term alcohol abusers. I-ney found that both young and old alcoholics displayed impairments on tasks that required the learning of new associations and their long-term retention. These deficits were apparent in alcoholics who had been abstinent for as long as seven years. Another important finding is that there may be an interaction between age and the recovery of cognitive function. One study found that alcoholics under 40 years of age recovered from most of their cognitive deficits within three weeks; however, those over 40 had not substantially recovered even after three months (Goldman, Williams, and Klisz, 1983~. Relationship Between Cognitive Impairment and Treatment Outcome The literature provides some indication that alcoholics with impaired neuropsychological function have poorer outcomes. Abbott and Gregson (1981) found a significant relationship between impaired cognitive function and poor treatment outcome at three months and at one year after treatment. Leber, Parsons, and Nichols (1985) asked experienced clinicians to rate alcoholic patients according to how they were progressing in theranv: they then compared the ratings with the result.c of n~llron~v~h~lnair~l tP~tina ~ ~ ~ ~ rid DO ^-I- I - ^a ~ . one patients who were rated as making the least progress were also those with the most impairment. Other studies have found weaker or absent relationships. Goldstein and Shelly (1971) found no relationship between cognitive function and ratings of adjustment one year after discharge; McLachlan and Levinson (1974) found no relationship between cognitive functioning and drinking/abstinence at one year. Walker and coworkers (1983) found a very modest relationship between cognitive impairment and outcome, but the strongest correlate of outcome was involvement in aftercare. Recent studies by Donovan, Walker, and Kivlahan (1987) have shown that the relationship between cognitive functioning and treatment outcome in alcoholics is complex. In general, Donovan's studies showed that cognitive functioning did not significantly predict alcohol consumption but did predict employment status. Similar findings showing a weak or absent relationship between cognitive functioning and outcome have been reported by Eckhardt et al. (198%~. In summary, although there is evidence that impaired cognition has a negative influence on outcome, this relationship is probably of varying strength, perhaps depending on such factors as the severity of impairment, the area assessed, and demographic or educational levels of the population studied. There are few available studies that attempt to relate cognitive status to a wide range of outcome measures. It would not be surprising to find that cognitively impaired patients do poorly in complex vocational or social situations, as noted by Donovan and colleagues (1987), whereas such patients perform similarly to those who are not impaired in less complex vocational situations. This entire area is one in which considerably more treatment research could be done. Treatment Programs and Cognitively Impaired Patients The overall structure of the treatment program may have an important interaction with cognitive function. Some work indicates that cognitively impaired alcoholics do best in a highly structured program, whereas nonimpaired patients do better in a less structured -276

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environment (McLachlan and Levinson, 1974). Although these findings are intuitively sensible, few studies have examined this area of patient-treatment matching in detail. Most residential rehabilitation programs last 28 days and include a significant amount of educational material, the dissemination of which begins early in treatment. This type of program may be inappropriate for some patients. Becker and Jaffe (1984) showed that alcoholics could not remember the information from a 55-minute film about alcoholism when it was shown during the first week of treatment. They suggested presenting information in small, easily assimilated chunks and in several different contexts within the treatment environment. They also believed that their results raised serious questions about the trend toward shortening the period of residential care. Similarly, Goldman and Rosenbaum (1977) argued strongly that new information should not be presented to alcoholics dunag the first several weeks following detonScation because of their impaired ability to remember and use the information. Very little information is available about how programs manage cognitively impaired alcoholics. For example, it is not known whether there are systematic differences between the ways cognitively impaired patients are managed in medically/psychiatrically oriented programs as opposed to freestanding programs. There is little information about the kinds of interventions or strategies most commonly used, and there is no information available about specific follow-up programs for cognitively impaired patients. Moreover, little is known about the use of formal cognitive assessment procedures by alcohol treatment programs. This area offers numerous treatment research opportunities. The following are opportunities for research on treatment and cognitive impairment: Further studies are needed on the relationship between cognitive status and treatment outcome. Do cognitively impaired alcoholics acquire new information and skills that help in their rehabilitation? Are they more likely to attend and benefit from Alcoholics Anonymous, a program in which simple, direct messages are constantly repeated? Studies are needed on how alcohol treatment programs deal with cognitively impaired patients. Are there treatment programs or techniques that do better (or worse) with cognitively impaired patients? Do programs that screen for cognitive impairment and then modify treatment accordingly do better with these patients than programs that do not? Does program structure make a difference? Cognitive Retraining If there are negative outcomes associated with impaired cognitive performance, treatment may be improved by techniques that can hasten or extend the normal recoverer process. There is a considerable literature on cognitive rehabilitation techniques for head injury (Rimmelle and Hester, 1987~. A detailed review of these studies is beyond the scope of this section, but there is good evidence that a variety of specific techniques can be used tO improve cognitive deficits. A few researchers have applied these techniques to cognitively impaired alcoholics with encouraging results. Godfrey, Spittle, and Knight (1985) found evidence that a memory training program increased the chances for a regular discharge in cognitively impaired chronic alcoholics. However, Yohman, Schaeffer, and Parsons (1988) found no significant changes in response tO memory training except in younger subjects. In other studies, Parsons (1987) found improvement in memory and problem solving in alcoholics who were -277

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given specific techniques designed for these problems. Goldman (198?) has summarized much of the literature in this area and has performed a series of studies which indicate that cognitive retraining techniques can result in gains greater than those to be expected from the normal recovery processes that accompany abstinence. He suggests that certain cognitive functions may not recover unless specific techniques are applied and that the recovery may be related to structural changes (e.g., dendritic arborization) that are stimulated by retraining techniques. The following questions represent opportunities for research on cognitive retraining: How effective are cognitive retraining techniques for cognitively impaired alcoholics? If these techniques are effective, how do they influence outcome? Nootropic Drugs Although not available at present, a new class of drugs to improve cognitive function (termed "nootropic" drugs) is now under development. Much of this work is being done to find pharmacotherapies for Alzheimer's disease. Drugs that act on the serotonin system may be important for alcohol clinical research, as indicated by studies showing that zimelidine can improve cognitive performance and that t~yptophan can reverse certain kinds of alcohol-induced memory impairment (Westrick et al., 1988; see also Linnoila et al., 1987~. Nootropic drugs could be used alone or in combination with retraining techniques, as has been done in studies with psychotherapy and pharmacotherapy. No promising candidates for clinical trials stand out at this time, but some drugs may emerge from the research on Alzheimer's disease. The following opportunities exist for research on nootropic drugs: As new drugs to enhance cognitive function become available, they should be studied in context with alcohol-induced cognitive impairments (including Korsakoffts disease). CARDIOVASCULAR EXAMS Chronic alcohol consumption adversely affects the cardiovascular system in three ways: (1) alcohol abuse is associated with hypertension and stroke; (2) alcohol ingestion can cause arrhythmias; and (3) chronic alcohol abuse can result in cardiomyopathy. However, it should also be recalled that epidemiological evidence suggests that people who have two drinks per day may have less coronary artery disease than nondrinkers (Rohan, 1984~. Hypertension In a large number of cross-sectional nonulatinn .ctildies on indP.nP.Dt1Pnt ~cqOri~tif~n hPh~PPn ~ ~ r-r~ _~ ~ r_ ~ In_ ^~^ V_ ~ __~& alcohol consumption and blood pressure has been reported (MacMahon and Norton, 1986~. A Kaiser-Permanente study of 84,000 persons (Klatsly et al., 1977) reported that the consumption of three or more drinks per day was associated with higher blood pressure: -278

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- blood pressure increased with increasing alcohol intake. At the level of six drinks per day, there was a twofold increase in the number of whites with hypertension and a 50 percent increase in hypertension in blacks. A small number of prospective, randomized controlled studies have evaluated the blood pressure effects of eliminating alcohol consumption (MacMahon and Norton, 1986~. Potter and Beevers (1984) studied 16 hypertensive men who drank up to 80 grams of alcohol daily. When alcohol consumption ceased, diastolic and systolic blood pressures decreased significantly. The reintroduction of alcohol resulted in significant increases in systolic and diastolic pressures. Alcohol-induced hypertension is probably partly responsible for the increase in stroke in heavy drinkers (Kozararevic et al., 1980; Donahue et al., 1986; Gill et al., 1986~. Gill and colleagues (1986) found that the relative risk of stroke, when adjusted for hypertension, cigarette smoking, and medication, was four times higher in heavy drinkers than in nondrinkers. Major advances have occurred in the past several years in the treatment of hypertension. Angiotensin converting enzyme (ACE) antagonists have been added to the therapeutic armamentarium of diuretics and beta blockers. The ACE inhibitors have an advantage over diuretics and beta blockers in that they usually have fewer side effects. The calcium channel blockers are not currently approved for treating hypertension, but they are effective for this purpose and will be approved shortly. Like the ACE inhibitors, they have relatively few side effects. The following are opportunities for research on hypertension: Studies should be pursued to determine the best treatments (and combinations of treatments) for hypertension associated with heavy drinking and alcohol dependence. Arrhythmias Alcohol is an arrhythmogenic agent. Acute alcohol ingestion can cause ventricular fibrillation (Singer and Lundberg, 1972) and a syndrome called the "holiday heart" syndrome, which is characterized by transient tachyarrhythmias occurring in individuals otherwise free of overt heart disease after periods of excessive alcohol ingestion. Electrophysiological studies have shown that the administration of alcohol can prolong conduction times (Engel and Luck, 1983) and sinus recovery time (Greenspon and Schaal, 1983~. Similar cardiac effects can occur during alcohol withdrawal (Van Thiel and Gavaler, 1985~. The ingestion of only 3 ounces of 80-proof whiskey caused atrial and ventricular tachyarrhythmias in 14 patients with a history of chronic alcohol consumption and palpitations or lightheadedness (Greenspon and Schaal, 1983~. It is likely that alcohol-induced arrhythmias are due to the direct toxic effects of alcohol on the myocardium and on the conduction system (Van Thiel and Gavaler, 1985~. Advances have been made in the development of new antiarrhythmic agents (e.g., calcium channel blockers for atrial flutter, and encainide or flecainide for ventricular ectopy). Encainide is 5 to 10 times more potent than previous antiarrhythmic agents, and effective doses have no untoward effects on blood pressure, heart rate, or intracardiac conduction (Woosley, Wood, and Roden, 1988~. Although antiarrhythmic drugs can suppress ventricular ectopy, any evidence that these agents improve survival in many of these types of patients is lacking (Woosley, 1988~. Those who are symptomatic probably do benefit, but suppressive therapy is of unknown benefit in asymptomatic patients. The important factor in preventing alcohol-related arrhythmias, however, is abstinence. Because with many -279

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patients abstinence cannot be ensured, there is a need to identify medication that would mitigate alcohol-related arrythmias. The following are opportunities for research on cardiovascular disorders: Electrophysiological monitoring studies could be used to precipitate arrhythmias with the administration of alcohol in a sample of individuals who are known to experience alcohol-induced arrhythmias. Studies could then be conducted to determine which antiarrhythmic drugs abolish the arrhythmia. LIVER EtPE;CI~S Alcohol abuse results in three histologic types of liver disease: (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. As described in the companion volume to this report (IOM, 1987), alcoholic liver disease is the most common cause of chronic illness and death from alcoholism. Approximately 8 to 15 percent of chronic abusers of alcohol develop liver cirrhosis, and most people who die from alcoholic liver disease have cirrhosis. The pathogenic mechanisms responsible for alcoholic hepatitis, fibrosis, and cirrhosis are presently unknown. Alcoholic hepatitis is a precursor (but not a prerequisite) in the development of cirrhosis. The current, generally accepted treatment for alcoholic hepatitis is supportive care, but research to identify effective treatment agents is in progress. One promising direction comes from evidence that alcohol consumption may induce pathological changes in the centrilobular area of the liver as a consequence of hypoxia (Israel et al., 1975~. As a result of increased hepatic oxygen consumption in other areas of the liver, Israel and coworkers (1975) found that propylthiouracil (PTU) rendered the centrilobular area more resistant to hypoxia and cell necrosis. Based on these findings, Orrego and colleagues (1987) evaluated PTU in patients with alcoholic liver disease. This study is important, not only because of reported benefits from PTU but also because the authors employed a rigorous research design that enabled them to separate the effect of the drug from the effect of abstinence or reduced alcohol consumption. The rigor of this research design should serve as a model for other studies in which experimental treatments are applied to alcohol-related pathology. For this reason, several important aspects of this study are described below. Patients were well characterized in terms of the presence of hepatitis, with or without cirrhosis. All patients were seen in a liver clinic in which compliance with drug treatment was measured by using a urinary drug marker (riboflavin). Among the 310 compliant patients (positive for riboflavin), the cumulative mortality in the PTU group was significantly lower (13 percent) than in the placebo group (25 percent). This reduction represented a 48 percent decrease in mortality in patients with moderate to severe liver disease. There was no significant difference in those with mild disease. Although patients were followed for up to two years, favorable survival was only seen early in this period. After 12 weeks, approximately the same number of deaths occurred in the drug and placebo groups. There was no significant difference in cumulative mortality between noncompliant patients in the drug and placebo groups. Of special importance is the finding of Orrego et al. (1987) that continued heavy drinking negated the beneficial effects of PTU. Drinking was monitored by testing daily urine specimens for alcohol. The ability of these investigators to obtain daily urine samples sets -280

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a new standard for treatment in trials of alcohol-related disorders. These findings demonstrate the importance of assessing both compliance with drug treatment and alcohol consumption in evaluations of drug treatments for alcohol-related pathology. It is also of interest that PTU was effective only in patients with a moderate degree of illness. An earlier study by this group (Orrego et al., 1979) found accelerated recovery with PlU treatment in hospitalized patients but no significant improvement in survival. Halle and colleagues (1982) Whiled to find any benefit from PTU in hospitalized patients. Thus, PTU is most effective In patients with mild disease or in those who are not ill enough to be hospitalized. There is no effective treatment for cirrhosis of the liver apart from abstinence from alcohol. Almost all studies examining the effects of abstinence on survival have found abstinence to be associated with longer life. What Is of great significance is that these studies also report a greater likelihood of long-term abstinence or reduced alcohol consumption in patients with cirrhosis compared with those alcoholic individuals of similar socioeconomic background who do not have this life-threatening illness. This pattern suggests that the development of a major complication of alcoholism may have a profound effect on drinking behavior. Liver Transplantation Liver transplantation has become an accepted treatment for end-stage liver disease, and the number of centers that perform hepatic transplantation is increasing. The timing of surgery is critical because transplantation should be reserved for those who are otherwise likely to live less than a year. Liver transplantation has not been done often in patients with alcoholic cirrhosis for two primary reasons. One concern was that patients with alcoholic cirrhosis had higher operative and postoperative mortality than patients with other forms of cirrhosis. The other reason was a fear that those with alcoholic cirrhosis would resume drinking and destroy the transplanted liver. These concerns may be unjustified. Starzl and coworkers (1988) have presented data that indicate that operative mortality is the same regardless of the type of cirrhosis and that this group has a very high abstinence rate. The following are opportunities for research on liver transplantation for alcoholic cirrhosis: What percentage of cirrhotic alcoholics who have received transplants return to drinking? What characteristics predict posttransplantation sobrietr? Complications of Cirrhosis The four most serious complications from hepatic cirrhosis in terms of mortality and morbidity are (1) hemorrhage from esophageal varices, (2) hepatic encephalopathy, (3) ascites, and (4) hepatorenal syndrome. At this writing, there are no specific treatment research opportunities that might be considered for a multicenter trial. Clearly, future treatment teals in these disorders should be designed by following the rigorous standards established by Orrego and coworkers (1987~. -281

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OTHER HEALTH CONSEQUENCES OF ALCOHOL ABUSE As described in the companion volume to this report (IOM, 1987), excessive alcohol ingestion adversely affects a number of other organs and organ systems including (1) the pancreas, (2) the heart, (3) the hematopoietic system, (4) muscle, (5) peripheral nerves, (6) bone, (7) stomach and esophagus, and (8) endocrine organs. It can also lead to impaired nutrition and is a major risk factor in injury-related deaths (see Chapter 2 on the epidemiology of alcohol-related problems). Heavy drinking is associated with acute and chronic pancreatitis; cardiomyopathy; abnormal gonadal function; impaired immunity; cancer of the mouth, pharynx, and esophagus; and other disorders. Advances in our understanding of the mechanisms for the deleterious effects of alcohol on these organs are well summarized in Causes and Consequences of Alcohol Problems (IOM, 1987~. Unfortunately, advances in treatment in these areas have not kept pace with knowledge about the role of alcohol as a critical risk factor. Abstinence remains the single most important goal in the prevention of these disorders. This emphasis underscores the importance of improving both the prevention and the treatment of alcohol dependence and problem drinking behavior. REFERENCES Abbott; M. W., and R. ~ M. Gregson. Cognitive dysfunction in the prediction of relapse in alcoholics. J. Stud. Alcohol 42~1~:230-243, 1981. Adamson, J., and J. ~ Burdick. Sleep of dry alcoholics. Arch. Gen. Psychiatry 28:146-149, 1973. Allen, R. P., ~ Wagman, L. A. Faillace et al. Electroencephalographic (EEG) sleep recovery following prolonged alcohol intoxication in alcoholics. J. Nerv. Ment. Dis. 153:424-431, 1971. Annis, H. M. The detoxification' alternative to the handling of public inebriates: The Ontario experience. J. Stud. Alcohol 40~3~:196-210, 1979. Annis, H. M., and R. G. Smart. Arrests, readmissions and treatment following release from detoxification centers. J. Stud. Alcohol 39~7~:1276-1283, 1978. Annis, H. M., N. Giesbrecht, ~ Ogborne et al. Task Force II Report on the Operation and Effectiveness of the Ontario Detoxication System. Toronto: Addiction Research Foundation of Ontario, 1976. Becker, J. T., and J. H. Jaffe. Impaired memory for treatment-relevant information in inpatient men alcoholics. J. Stud. Alcohol 45:339-343, 1984. Begleiter, H., and B. Porjesz. Persistence of a Subacute withdrawal syndromes following chronic ethanol intake. Drug Alcohol Depend. 4:353-357, 1979. Brandt, J., N. Butters, C. Ryan et al. Cognitive loss and recovery in long-term alcohol abusers. Arch. Gen. Psych. 40:435-442, 1983. Brown, M. E., R. F. Anton, R. Malcolm, and M. Ballenger. Alcohol detoxification and withdrawal seizures: Clinical support for a kindling hypothesis. Biol. Psychiatry 23~5~:507-514, 1988. -282

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