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[CANCER RESEARCH 39, 2836-2839, July1979] 0008-5472/79/0039-0000$02.0O The Disease of Alcoholism1

Stanley E. Gitlow

Mount Sinai School of Medicine, New York, New York 10029

Abstract ance to all of the remaining despite the possi bility that none of the other drugs listed in Table 1 has ever A pharmacological view of addiction and , been tried. Setting the issue of tolerance aside for the moment, or addiction, serves as a basis for the further exami let us examine dependence. Not only may the narcotic drugs nation of these complex illnesses. The disease called produce and the incumbent withdrawal ism (sedativism) consists, however, of much more than just a syndrome upon discontinuation of the agent, but a cross-de chronic or periodic addiction to a sedative . The urgent pendency exists between the various members of the narcotic need to understand the psychological and societal parameters group. Thus, one may replace one narcotic with another and of this illness is underscored by the likelihood that alcoholism thereby prevent the withdrawal syndrome from appearing. This represents the major factor in the cause of of young results in a variable degree of cross-addictability, the patient adults (<45 years) in the United States today. Its further role addicted to one narcotic agent being relatively willing to main as a carcinogen is only recently achieving adequate examina tam his addiction by use of any other narcotic despite the fact tion. that minor preferences may exist. As with the narcotic group, the sedative group also demonstrates physical dependency Although plaguing mankind since antiquity, 2 major illnesses and cross-addiction within the group of soporific drugs. Thus, of addiction continue to exact their terrible cost without either one may replace an i.v. drip with pentothal without broad understanding of their nature or appropriate efforts permitting the withdrawal syndrome to appear and without directed toward their control or eradication. Perhaps the more seriously inconveniencing the patient's feeling of well-being. recent of these, involving many thousands of Americans, has Patients with alcoholism discovered the cross-addictability of been accompanied by sociopathic behavior with its resultant the sedative drugs much earlier than the medical profession. strain upon the legal mechanisms for dealing with ethical so As early as 25 years ago, it was apparent that many affluent, cietal problems. It has been called ‘‘drugaddiction,'‘although urban patients with alcoholism were establishing dependence the illness involves addiction to only the narcotic compounds upon sedative agents other than ethanol. During the past (, meperidine, , , etc.). The other, quarter of a century, the incidence has risen from about 35% involving millions of victims in the U. S. alone, entails addiction to somewhat in excess of 50%. to any one or a combination of sedative-soporific drugs (Table In questioning the existence of the so-called ‘‘addictiveper 1) and has been called, also inappropriately, alcoholism. The sonality' ‘some20 years ago, it was startling to realize the media, perhaps because of the long social use of alcohol, have rarity with which one observed either a crossing over from one quite consistently confused the 2 addictions by referring to group of substances to the other or the simultaneous use of alcoholism on the one hand and drug addiction (grouping sedative and narcotic agents, except in those instances involv with solid ) on the other. Of course alcohol ing physicians and nurses wherein drug availability might well is a drug, and, more seriously, this view obscures the basic have played a special role. With the advent of methadone nature of the disease of alcoholism as well as the critical programs, however, cross-addiction between these 2 major relationship among sedative drugs in general. From a phar classes of drugs became either more frequent or more visible. macological standpoint, the 2 groups of drugs are quite dis Even then, alcohol or other sedative abuse among patients parate. Narcotics will classically produce analgesia without taking methadone for the treatment of their narcotic addiction substantive whereas sedative-hypnotic drugs can only achieved no more than a 35 to 40% incidence. The majority of produce significant analgesia after eliciting a somnifacient re such addicts failed to turn to the sedative drugs despite the suIt. There are certain similarities to the addictive state pro fact that methadone in no way interfered with their doing so. It duced by each of these groups, however. The narcotic agents might also be stressed that there is no substantive cross can elicit a 20-fold increase in tolerance, and there is cross tolerance or cross-dependency between the sedative drugs on tolerance among the various drugs of this group. Thus, when the one hand and the narcotic agents on the other. The ad one has achieved considerable tolerance to methadone, there dictive illness that we discuss is that to sedative drugs. The is simultaneously increased tolerance to heroin and the other material which follows is largely the clinical bias emanating drugs in the narcotic group. In the case of the sedative drugs, from in excess of 25 years of treatment of many hundreds of tolerance can be established, but it can rarely achieve more patients suffering from this illness. than a 2-fold increase. Cross-tolerance within the group of Alcoholism is a disease (3) characterized by the repetitive sedative agents also occurs, having first been observed during and compulsive ingestion of any sedative drug, ethanol being the 19th century when physicians attempted to anesthetize the just one of these, in such a way as to cause interference in with the then new agent, . The fact is, some aspects of the subject's life, be it in the area of interper when one is tolerant to alcohol, there is simultaneously toler sonal relationships, job, marriage, or physical health. It is absolutely critical to appreciate that this definition does not in any way specify which sedative agent is used, the frequency I Presented at the Workshop, October 23 and 24, 1978. Bethesda,Md. of its use, or the amount ingested. Thus, patients with this

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Table1 technically correct would be that of ‘‘sedativism'‘(2)if, only to drugs emphasize that patients with this illness may replace alcohol Ethanol with not only any one of its variant beverages but with any hydrate other soporific drug as well. Alcoholics often refer to Librium (short, medium, and long acting) as simply ‘‘theverydriest martini. ‘‘Themajor differences (Doriden) resulting from such a replacement reside only in their relative (Placidyl) caloric content and perchance their odor. Less facetiously, we (Noludar) (Librium, Valium, etc.) should recognize that the alcoholic who has switched from (Equanil, Miltown) ethanol to benzodiazepines may well have leaped from the frying pan into the fire. Except among adolescents, there is Diethyl ether little of a rewarding social milieu during pill taking, and the alcoholic, by passing this particular barrier of social accept ance, may simply have indicated something more about the illness come in all sizes, shapes, and colors. They may be 8 or severity of his compulsion and the unlikeliness with which he 80 years old. The amount ingested per year might be consid might respond to therapeutic efforts. Obviously, the term al erably less than even the most modest social drinker's yearly coholism is perfectly adequate as long as we all realize that intake. Alternately, one may observe substantive tolerance and nothing more than historical coincidence favored it over chlor a regular daily ingestion of enormous quantities of soporific alism, barbism, or paraldehydism. Since the colorful stores, drugs. The key issue in the definition is that of ingesting a packages, and advertisements dealing with sedative use con sedative agent despite the fact that previous experience should sistently limit their attention to ethanol as opposed to the other have more than clearly demonstrated a serious untoward result sedative drugs, let us examine this particular drug as a proto from the drug. One need drink but twice per year, and, if such type of the group. drinking is associated with motor vehicle operation, or lion An understanding of the clinical of ethanol (1) taming, the modest incompetence of excessive sedation could is essential to the comprehension of the disease of alcoholism. well yield catastrophic results. It also must be stressed that the We need concern ourselves minimally with the action of this subject must have had ample opportunity to observe the unto substance upon any tissue in the body other than that of the ward results on one or more previous occasions before such . It may be facetious, but it is true that no one ingests this behavior could fall within the confines of this diagnosis. As with chemical for what it does to his liver. Fortuitously, ethanol is so many other diseases, this particular one has a spectrum of rapidly absorbed and achieves appreciable central nervous severity, that associated with the least severe aberration and system levels within a short time after it is ingested. At that function obviously being the most difficult to diagnose. In its point, it yields its primary and major pharmacological effect, mildest form, functional impairment might fail to appear in any that of sedation. There is considerable popular confusion con area other than that of lost potential. cerning this sedative effect of alcohol, since individuals vary in Many patients with this illness, in their attempts to control their psychological response to sedation. One subject will the difficult or even disastrous results of their drinking, turn to notice a surge of energy whereas another will find himself more convoluted behavior for safety. Thus, they may switch from able to . Suffice it to say that the psychological response hard to or or attempt to limit the number of to sedation may vary, but the dominant pharmacological re their drinks as well as the day or time of day during which these sponse of the central to ethanol during the first may be ingested. Drinking may, under those circumstances, few hr after its ingestion is always that of sedation. If enough become dependent upon specific demands at work or the sedative is taken at this particular time, it will result in somno availability of a ‘‘nursemaid'‘athome. Such subjects will often lence in all subjects. During this period, the response of animals become what is casually known as ‘‘periodics.‘‘Theirtotal to ethanol is one of increasing the electroconvulsive threshold yearly alcohol intake might be quite modest, but the functional (9). No matter how much ethanol one administers to a mammal, impairment of their lives might still be and often is extreme. the sedative action of a nonlethal dose persists for no more Since this conference deals with the relationship of alcohol and than 5 hr and usually closer to 2 hr. The implication of this is cancer, it is probably well to bear in mind that one may not that, within 2 hr of the last drink of alcohol, maintenance of the make the assumption of a direct correlation between total sedative action requires another dose. It has always been alcohol ingestion and the diagnosis of alcoholism in any spe somewhat intriguing to realize that the alcohol level cific instance, except in those circumstances wherein the achieves its peak value at about the end of 2 hr, the very time ingestion of this drug is high enough to elicit severe and at which the sedative action of the drug starts to disappear. consistent pharmacological problems. It is therefore entirely Those very blood concentrations of ethanol associated with possible that from a public health standpoint one might observe substantive sedation during the first hr after alcohol ingestion a society in which the ‘‘social'‘useof ethanol is high enough (during rising concentrations) may well fail to sustain any to elicit untoward oncological problems without an overwhelm sedative action whatever 2 hr later when the blood alcohol ing incidence of alcoholism. The difficulty in correlating total concentrations are diminishing. Another clinical pharmacolog alcohol consumption and the incidence of alcoholism has been ical action of ethanol becomes apparent after the sedative noted not only in national groups (France, Italy, and Spain) but effect wears off. It consists of agitation, or increased psycho also in subcultures within this country as well (American Jews motor activity. The increased psychomotor activity state per versus American Irish). Let us nonetheless return to the primary sists for approximately 12 hr, but its amplitude is low. We thus issue at hand, an examination of the disease called alcoholism. see that ethanol has a complex and asynchronous action upon As we have seen, the term alcoholism is a misnomer. More the : a large-amplitude, easy to observe,

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1979 American Association for Cancer Research. S. E. Gitlow short-acting sedative effect; and a low-amplitude, difficult to the continued use of ethanol in large quantities over a pro detect, long-acting agitating effect. Repeated use of the seda longed period of time results in a gradual increase in the tive drug on an every-other-hr basis would result after 12 hr in psychomotor activity level of that individual. Such agitation may the disappearance of almost all of the sedative actions of 6 well be difficult for the naive observer to appreciate while separate drinks, but there would be persistence of their agitat current doses of sedative are being consumed. When such ing effects for many hr thereafter. This dichotomous and asyn sedation is discontinued, however, the elevated psychomotor chronous effect of sedative drugs is responsible for the so activity level appears in all of its florid glory, and the subject called withdrawal syndrome. Since the withdrawal syndrome demonstrates all the phenomena associated with the with starts with Dose 1 of the sedative agent and since its very drawal syndrome. When mild, these may consist of no more appearance coincides with peak blood levels of this drug, the than tremulousness, , tachycardia, , hyperten term withdrawal syndrome is obviously another misnomer. sion, entercolitis, and minimal evidence of an organic mental Quite apparently, the increased psychomotor activity level as syndrome. In its more extreme form, these manifestations may sociated with the use of alcohol represents an inherent part of be joined by acute hallucinosis. Its extreme state includes a the pharmacological action of the drug. Indeed, animals metab toxic known as tremens. All of these states olizing alcohol at rates as great as 10-fold faster than humans are associated with an elevated incidence of activity. nonetheless demonstrate the same temporal sequence of Se The degree of severity attained with this syndrome appears to dation and agitation as does the human. The action of ethanol vary with the age of the subject, the duration and amount of upon the brain then must be conceptualized as analogous to sedative ingestion, and other aspects of general physical that of pulling a trigger on a gun: after adequate motion of the health. finger has taken place, the sequence of events and the firing Although minor fluctuations in tolerance may stem from of the projectile bear no relationship to further activity of the individual variations in or even enzyme induction, digit. Thus, there is little benefit to be derived from detailed there is no question that the most significant and critical cause studies of the metabolism of alcohol. Its zero order kinetics of of tolerance is related to central nervous system adaptation. A catabolic degradation, pathways, or even sites of its degrada clinical pharmacological understanding of this can best be tion and excretion are reasonably unimportant. This is espe attained if one simply considers the balance between the cially true if one bears in mind that at any point in this sequence sedative and agitating effects of alcohol. It is quite apparent of events one may replace the substance with some other that the individual who has achieved substantive agitation due soporific having enormous differences in its catabolism, excre to previous alcohol ingestion might tolerate considerable cur tion, and kinetics. rent sedation (i.e. , ethanol dose) without achieving that degree Animal investigations can clearly demonstrate that it requires of sedation that is no longer compatible with maintaining life. only extremely small amounts of sedative agents, ethanol or Thus, it is not unusual to observe heavily drinking individuals short-acting barbiturates, to be followed shortly by evidence of with blood alcohol levels as high as 0.7%, who, at that moment, increased psychomotor activity. This agitation may be seen in continue to maintain physical activity. Obviously, the metabolic the human subject if one carefully observes clinical behavior rate affecting any of the sedative agents cannot have much to following ethanol ingestion. Although one may not notice a do with that type of tolerance. On the other hand, enzyme

‘‘' ‘the morning after the New Year's Eve party, there induction as well as vying for common catabolic pathways can is little doubt that such an individual will arise relatively early result in an extremely complex relationship between competing on New Year's Day and will notice a vague of foreboding sedative agents. The danger inherent in the concomitant use along with his modest agitation. These sensations tend to wear of ethanol with other sedatives is too well known to bear off early in the afternoon unless the subject chooses to take repetition at this point, especially since much of our knowledge current sedation to rid himself of the agitation remaining from about this stems from the efforts of one of the speakers at this the previous evening's sedation: the . That conference, Dr. Charles S. Lieber (see Ref. 6). individual unable to tolerate his own base line state of psy Although Dr. Isbell's studies clearly demonstrated the re chomotor activity may well utilize alcohol as a means of achiev sponsibility of ethanol in producing the withdrawal syndrome, ing a more comfortable status. Unfortunately, the cost of such he failed to call upon his subjects to revolunteer for yet another a pharmacological adjustment of one's psyche is simply that of drinking bout after recovering from the severe withdrawal state further agitation, a circumstance unlikely to be welcomed by emanating from the original episode of alcohol ingestion. The that very subject unable to tolerate even his control level of natural hesitancy or even refusal of most subjects to comply . Thus, we hear the phrase in of with such a request might offer insight into the ease with which

‘‘one drink never being enough but always being two much.― we can convert the human volunteer into an alcohol addict but It should also be clearly appreciated that, regardless of the not into the patient with alcoholism. To accomplish the latter psychic response of the individual to sedation (be it somno requires that the subject return over and over and over again lence or the hyperactivity associated with release of inhibi to the sequence of circumstances invariably leading to illness tions), the desired central nervous system effect is that asso and distress. That compulsive return to the scene of the crime, ciated with sedation. No one drinks alcohol for its effect the so to speak, despite any and all costs represents the inherent morning after. The ‘‘reward,‘‘thedesired effect, comes con difference between simple addiction in the volunteer and the comitantly with its sedative action during the first 2 hr after its disease of alcoholism. It is as though the individual with the ingestion. illness is somehow unable to learn that this particular coping It remained for Isbell (5) to demonstrate about 25 years ago mechanism is repetitively and consistently followed by such that the intake of nutrients had little if any relationship to this adverse experiences. Since there is little doubt that there is no pharmacological effect of ethanol upon the brain. Obviously, intellectual deficit among subjects with alcoholism, one must

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look to other factors for an understanding of this phenomenon. drink will eventually lead to loss of control. The fact that such It has been known for some time that over three-quarters (7) of an individual continues to tempt fate in such a disadvantageous any probands with alcoholism have at least one family member manner serves as a measurement of his compulsive behavior. who also suffers from this illness. Dr. Donald W. Goodwin is at As with any compulsive acting out, the opportunity to resist is this meeting, and I am certain he will relate some of his always greatest at the initial moment. interesting studies which have suggested a genetic predispo Many years ago, I was asked to review the records of those sition to this disease. There is also more than adequate evi patients for whom my efforts failed. I was shocked to discover dence that various societal and psychiatric factors must be that the outcome for many of these individuals was sudden considered in its etiology. In general, the characteristics of the violent death. Their varied from those associated with alcoholic, despite a tendency to dependence, , and falls and motor vehicle accidents to purposeful or accidental isolation, have failed to achieve a specific enough structure to , as well as becoming a torch when their lit cigarette permit detection of the disease prior to its clinical stages. entered the couch or bed linen during their sedation. Indeed, Nonetheless, the genetic, societal, and psychiatric data which if one were to add the 50% of motor vehicle deaths, the 60% we presently possess all offer prophylactic and therapeutic of drownings, the 85% of deaths from hepatic , the possibilities for the eventual control of the illness. burns, the suicides, and the murders, one might begin to It is well to bear in mind that some of the typical character appreciate that alcoholism represents the major cause of death istics of alcoholism stem from the progressive loss of tolerance of all young adults in the United States today. Certainly such a to sedative drugs which follows upon aging. The patient ob circumstance would hold true for the age category of 15 to 45 serves but often fails to appreciate that less alcohol is required years. The Medical Examiner's Office of the City of New York for achieving drunkenness, the duration of gratification be recently substantiated this type of observation (4) and made a comes shorter, and the degree of discomfort the following day plea for a change in our documentation and record keeping of is both greater and of longer duration as be becomes older. In causes of death to enable us to appreciate the magnitude of this sense, alcoholism is a self-limited disease; there is no way this onslaught. If we now also demonstrate a relationship be to attain the tolerance of youth once lost. This mechanism may tween alcohol ingestion and carcinogenesis, it would seem that explain in part why alcoholism has been termed a ‘‘progressiveas a nation the United States should be devoting considerably disease. ‘‘Suchreference on the other hand might also stem more than the precious little effort, time, and money which we from the possibility that long-term use of large quantities of have in the past decade. ethanol might result in subtle central nervous system damage. This injury appears to be most similar to the organic mental defect associated with senility. Most patients, having lost their References tolerance by their mid-40's, seek medical assistance at about 1. Gitlow, S. E. Treatment of the reversible acute complications of alcoholism. the time that they have also lost normal attention span, ability Mod. Treat.,3:472, 1966. to concentrate, and recent memory. 2. Gitlow, S. E. The pharmacological approach to alcoholism. Md. State Med. J.,19: 103-106, 1970. Although there is little doubt that this chronic, recidivistic 3. Gitlow, S. E. Alcoholism: a disease. In: R. Fox and P. G. Bourne (eds.), illness responds to therapeutic intervention, its effective treat Alcoholism: progress in research and treatment. New York: Academic Press, ment at present depends upon an ethical and spiritual program Inc., 1973. 4. Haberman. P. W., and Baden, M. M. Alcohol, other drugs and violent death. rather than drug therapy. Unfortunately, a small group of be New York: Oxford University Press, Inc., 1978. haviorists (8) has failed to understand the clinical characteris 5. Isbell, H., Fraser, H. F., Wikler, A., Belleville, A. E., and Eisenman, A. J. An @ tics of the illness and has therefore aimed toward the devel experimental study of the etiology of ‘rumfits'‘anddelirium tremens. 0. J. Stud. Alcohol, 16: 1, 1955. opment of training programs designed to assist the alcoholic to 6. Lieber, C. 5., Seitz, H. K., Garro, A. J., and Womer, T. M. Alcohol-related continue so-called controlled drinking. This has been partially diseases and carcinogenesis. Cancer Res., 39: 2863—2886,1979. 7. Lucero, R. J.. Jensen, K. F., and Ramsey, C. Alcoholism and in based upon the ludicrous assumption that the ‘‘medicalmodel― blood relatives of abstaining alcoholics. 0. J. Stud. Alcohol, 32: 183, 1971. of alcoholism implies thatthe first drink inevitably and invariably 8. Marlatt, G. A., and Nathan, P. E. Behavioral Approaches to Alcoholism. New leads to uncontrolled drinking by the alcoholic. Of course, such Brunswick, N. J.: Rutgers Center of Alcohol Studies, 1978. 9. McQuarrie, D. G.. and Fingl, E. Effects of single doses and chronic admin a circumstance characterizes extremely few of these patients. istration of ethanol on experimental in mice. J. Pharmacol. Exp. Rather, the alcoholic can never be certain as to which first Ther.,124: 264, 1958.

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Stanley E. Gitlow

Cancer Res 1979;39:2836-2839.

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