Appendix A

Some Basic Problems in Drug Addiction and Suggestions for Research*

by MORRIS PLOSCOWE

IV. THE NATURE AND CHARACTERISTICS OF DRUG ADDICTION

The law has largely acted on the premise, which is supported by some of the earlier writers, that drug addiction was largely a vice, which an effort of the will could conquer. Severe penalties were necessary to compel the will to make the effort to conquer the vice. Medical writers, on the other hand, have taken the view that drug addiction was a disease and that the drug addict was a sick person. For example, Emest S. Bishop wrote many years ago: "The fundamental truth which applies to all cases of narcotic drug addiction is this--whatever may have been the circumstances of the primary administration of narcotic drugs, or whatever the physical, ethical or personal status of the person addicted... Continued administration of the drug creates within the body of the person to whom the drug is administered a physical disease process. A demonstration of material cause and effect in obvious symptomatology, in physical suffering, and in nerve strain and exhaustion, unless there is applied to that person in sufficient amounts the drug of his addiction. Every addict is sick of a disease condition... insufficiently recognized and insufficiently studied."22 Or as Dr. William G. Somerville put it: "Drug addiction is a disease, a pathological condition just as much as the psychoneuroses of any of the various toxic states."23 If the physiological and psychological need for the drug inherent in drug addiction is a disease, then it will be apparent from our discussion of relapse that it is a disease which is largely incurable by present methods and techniques. The course of the disease can only be controlled by the continued administration of the drug of addiction or some similar drug.

There are, however, many who do not regard drug addiction as a disease entity. Maurer and Vogel for example have pointed out that: "All the research done on drug addiction within the past two generations indicates that addiction is not a disease, rather a symptom of personality difficulties, which if they did not lead to drug addiction would lead to difficulties of other types."24

Maurer and Vogel would say that drug addicts are sick, unbalanced, disturbed, abnormal individuals. Unfortunately as we shall see in our discussion of the personality types of drug addicts (infra), it is easier to attach a psycho-pathological label to the drug addict than to explain how or why he became addicted or why he continues his addiction.

Many with similar psychological difficulties do not become addicted to drugs. Some become alcoholics rather than drug addicts. The mere designation of a drug addict as a sick, unbalanced, disturbed or abnormal individual conceals more than it reveals. This is clearly indicated by the comments of Dr. H. Isbell: "Addiction is a complex process in which pharmacological, psychological, socio-economic and legal factors play interdependent roles. It is viewed in two ways: (1) as a distinct disease; (2) as a symptom of an underlying personality disorder.

Both views can be supported by evidence established so far. Studies have shown that the majority of addicts have personality disorders which antedate drug use. Also, addicts use many drugs and change from one to another especially when their favorite drug is difficult to obtain. Drugs used by addicts also have diverse actions; they not only use drugs that cause 'depression' but also stimulants. The only common denominator among drugs abused by addicts seems to be that they all are compounds which exert powerful effects on the central nervous system. These facts suggest that there is nothing specific about the drugs that addicts take and, therefore, addiction is nothing more than a symptom of the personality disorder. This view cannot be accepted without reservation. The theories of personality that are used to explain addiction are the same theories that are used to explain neurosis, psychoses, character disorders, etc. Since it is known that many persons with personality characteristics similar to those of addicts never abuse drugs, it is apparent that factors other than personality must be operating. Furthermore, under conditions of equal drug exposure, one individual may choose opiates, another alcohol. This implies some sort of specificity in the choice of the drug of addiction."25

Whether addiction to drugs be viewed as a disease or as a symptom of personality disorder it usually involves the three characteristically related phenomena, noted in the definition of the World Health Organization, namely, (1) tolerance, (2) physical dependence and (3) emotional dependence. These phenomena have been described by Isbell and White as follows: "By tolerance is meant a decreasing effect on repetition of the same dose of a drug. This particular characteristic is very marked in addiction to the opiates and synthetic analgesics.

Patients with well developed tolerance have injected as much as 5 gm. (78 gr.) of morphine sulfate intravenously in less than twenty-four hours without developing significant toxic symptoms. Tolerance to the various effects of morphine and related drugs develops, however, at different rates and in different degrees. For example, tolerance to the toxic, sedative, emetic, analgesic and respiratory-depressant effects of morphine develops very rapidly and becomes marked, whereas tolerance to the miotic effects and to the spasmogenic effects on gastro-intestinal smooth muscle, if developed at all, is never complete. "Physical dependence refers to the development of an altered physiologic state which requires continued administration of a drug to prevent the appearance of a characteristic illness, termed an 'abstinence syndrome.' Physical dependence is an extremely important characteristic of addiction to morphine and similar drugs, since it leads to continuity of intoxication with resultant subservience of all phases of the addict's life to the one aim of obtaining and maintaining a constant supply of the drug.

"Emotional dependence is defined as a substitution of the use of the drug for other types of adaptive behavior. In other words, use of the drug becomes the answer to all of life's problems. Instead of taking constructive action about his difficulties, regardless of their type, the addict seeks refuge in his drug."26 It is simpler to describe the phenomenon of tolerance to and physical dependence upon opiate drugs, as Isbell and White have done, than to explain the exact mechanics of their action upon the human organism. A great deal of research has been done on both phenomena in the attempt to find such explanations. Much of value has been uncovered by this research. Nevertheless, the fundamental effects of narcotic drugs upon the human system are still obscure. As Maurer and Vogel have noted: "The action of the opiate drugs and their synthetic equivalents upon human beings is still imperfectly understood. This fact is striking when we consider that opium has been used generally for thousands of years, and that no single medicine is more useful or more generally used by the physician than the modern opium derivatives and opium-like synthetics .

Certain fundamental questions are still unanswered; many peripheral or incidental problems remain to be solved. With some of the basic reactions of opiates upon the human physiology and neurology still obscure, it is not surprising that the nature of addiction to drugs of the opiate series ...should still be a controversial matter. The nature of narcotic addiction is still not yet fully understood."27* *"An examination of Nathan A. Eddy's classic chapter on tolerance and addiction, which summarizes the studies up to 1940, indicates the soundness of the above observation. Dr. Eddy wrote as follows: "The last word has not been said by any means on the mechanism of tolerance and addiction to morphine. Evidence is accumulating that morphine is handled differently in the tolerant animal. In addition, the phasic character of morphine action (excitation on the one hand, and apparent depression on the other hand), seems to be intimately concerned in the tolerance development and addiction, whether it is a question of the time relations of the two effects or of an alteration of the biologic substrate. The disturbed autonomic and hormone balance in addiction and withdrawal needs further careful thorough study."28 Commenting on tolerance, Dr. Eddy stated: "The evidence as a whole points to a change in the cells of the nervous system as the important factor, but the exact nature of the change and its fundamental mechanism are still unknown." In the same volume as Dr. Eddy's study, Margaret Sumwalt analyzed the studies which attempted to answer the question of what the organism does to morphine. She pointed out that man disposed of between 1/3 to 1/10 of his intake of morphine in his urine and feces. Sweat and saliva carry trivial amounts. Milk perhaps more.

"The remaining 65 to 85% is got rid of rather promptly by unknown chemical processes ... The chemistry of morphine metabolism is unknown."29 The present status of research on tolerance and dependence is clearly summarized by Isbell, in his authoritative article, "Trends Research On Opiate Addiction." "Most physiological research in addiction has been concerned with tolerance and physical dependence. Two major hypotheses have been developed. The first is that of Tatum, Seevers and Collins and is based on the dual character of the effects of morphine on the central nervous system. Morphine has both excitant and depressant effects within the central nervous system. In animals, the excitant effects appear to outlast the depressant effects. Therefore, as morphine is repeatedly administered, the excitant effects constantly increase. This excess excitation requires more and more of the drug in order to obtain the excitant effects, which are still present, and unopposed by depressant effects; hence, abstinence symptoms occur. Recently this hypothesis has been expanded. It is conceived that morphine exerts its depressant effects by attachment to receptors within the cells. The drug at receptor sites on the cell surface is in equilibrium with drugs in body fluids, is easily detached and swiftly metabolized. Morphine hypothetically diffuses into and out of cells quite slowly, so that degradation of drug attached at this site is slow. Since drugs on the cell surface are more rapidly dissipated than are drugs within the cells, the excitant effects outlast the depressant. Unfortunately this concept is completely untestable with present technics, and there are also objections to the 'depressant-excitant' formulation. In the lower animals, codeine is a more excitant drug than is morphine. One would therefore, assume that symptoms of abstinence from codeine would be more severe than symptoms of abstinence from morphine; actually, the reverse is the case. Also, in the chronic spinal dog, morphine markedly enhances-'stimulates'--the ipsilateral extensor thrust reflex.

"If this is regarded as an excitant action of morphine, the reflex should be even more hyperactive following withdrawal of the drug. Actually, the extensor thrust reflex disappears during abstinence. "The other theory of tolerance and physical dependence was first formulated by Joel and Ettinger and has been further developed by Himmelsbach. In this formulation, it is hypothesized that the administration of morphine calls into play homeostatic responses which oppose the effects--chiefly the depressant effects--of the morphine. These homeostatic responses are gradually strengthened by repeated administration of the drug and, therefore, more drug is required to induce the initial degree of effect. When morphine is removed, the enhanced homeostatic responses still remain and are released from the brake imposed on them by the continued presence of morphine in the organism, thus accounting for symptoms of abstinence. This formulation seems to fit the facts. For example, morphine constricts the pupils and depresses respiratory rate in minute volume. When morphine is withdrawn, the pupils dilate and hyperpnea ensues. Many other examples could be stated. In fact, the development of counter responses which oppose the main effects of drugs may be a general pharmacological phenomenon... It is apparent, however, that the homeostatic theory is more descriptive than explanatory. It tells us what happens but not really how. We have very little knowledge of the mechanisms of the homeostatic responses that supposedly oppose the actions of morphine. Due to the researches of Wikler, we can describe them in neurophysiological terms. In the non-addicted chronic spinal dog, morphine enhances the extensor reflexes, and has little effect on the knee jerk. It can be inferred from these facts that morphine depresses reflexes which are mediated through multi- neuron arcs (the flexor) and has little effect on reflex arcs that are mediated through a single synapse (the patellar). As tolerance develops, multineuron arcs become hyperexcitable and, on withdrawal of the morphine, excitability in these arcs is unmasked and accounts for withdrawal symptoms. Similar phenomena have been observed in spinal man. It is also known that chronic decorticated dogs develop tolerance and symptoms of abstinence on withdrawal of morphine. One may infer therefore, that the cerebral cortex is not necessary for the development of physical dependence. Although these facts give us some concept of the neurophysiological changes associated with addiction we know little about the nature of the changes at levels between the cord and the cortex. Technical difficulties in studying the activity of these levels in chronically intoxicated animals have not yet been solved, but the current trend in neurophysiological research in addiction consists partly of attempts to develop such methods.

"Biochemical studies have shown that tolerance and physical dependence are not related to changes in excretion or distribution of morphine within the organism, and are also not due to any known degradation product of morphine. Eisenman and Fraser have shown that maintained addiction causes a decrease in the urinary excretion of 17-ketosteroids, 17-hydroxycorticoids, and of pituitary gonadotropin although the adrenal and the gonads remain responsive to ACTH and chronic gonadotropin. On withdrawal of morphine, excretion of 17-ketosteroids is increased, serum corticoid levels rise and eosinophile counts decrease. These results indicate depression of the adrenals, the gonads or both by morphine during maintained addiction probably because of depression of the pituitary through unknown central mechanisms. During abstinence, there is a marked adrenal discharge. These findings are very important since they explain the decreased libido and sexual activity present during opiate addiction. The psychiatric significance of this effect requires no comment. "Efforts to elucidate the biochemical mechanisms underlying dependence and tolerance have not yet proved fruitful. Though the technical difficulties are great, studies of this sort are now being pushed. Obviously, we cannot explain all the phenomena of addiction by physiological data alone. Physiological data, though very useful in understanding symptoms and in managing them, contribute to total understanding of the problem only insofar as correlation of physiological mechanisms with drug induced changes in behavior are possible. "30 Whatever the mechanics of tolerance and dependence, if the addict has reached the stage of physical dependence upon a drug, he must obtain the drug regularly if he is to avoid the distressing experience of the withdrawal syndrome. How much of the drug he will use, will depend in the first instance on how much he can get. If the drug is available, despite the mechanism of tolerance, each addict eventually tends to find a level or a physical plateau in the use of the drugs. He tends to stop increasing the dosage at a point where he feels right physically and psychologically or where the drug will give him the euphoria that he is looking for. But whatever his level or plateau, the addict must obtain enough drugs to ward off the withdrawal symptoms which inevitably follow any failure to obtain the drug.

The withdrawal syndrome or sickness is no mere figment of the addict's imagination, but an illness which constitutes one of the most stereotyped syndromes in clinical medicine.

Wikler has demonstrated that physical dependence is a real physiological entity and is not psychic in origin. He has distinguished the purposive from the non purposive features of the withdrawal syndrome as follows: "The train of events which follow abrupt cessation of morphine in the tolerant addict varies within limits in different individuals, and is related to previous dosage, duration of addiction and the degree of tolerance which had been developed. However, for any given dose level and period of addiction, the morphine abstinence syndrome is remarkably reproducible in any given individual. The significance of the morphine abstinence syndrome to the individual is also highly individualized and is partly determined by particular situations. Thus, it may serve as a means for expressing hostility, expiating guilt and even justifying relapse. When observed in a hospital situation after abrupt and complete withdrawal of the drug, the fully developed morphine and abstinence syndrome is characterized by the following changes, which may be separated into two groups: "

(a) NON-PURPOSIVE. These consist of yawning, lachrymation, rhinorrhea, mydriasis, gooseflesh (piloerection) tremors, muscle twitches (particularly in the lower extremities), restlessness, hot and cold flashes, nausea, vomiting, diarrhea, anorexia, weight loss, ejaculations in men and orgasms in women, elevation of body temperature, cardiac and respiratory rates and blood pressure, leucocytosis, hemoconcentration, elevation of blood sugar and a precipitous drop in circulating eosinophile count. In addition, the subject often exhibits a rather typical facies suggestive of an individual with an acute febrile infectious disease. Often the patient 'curls up' in the lateral recumbent position with a blanket drawn over his head, preferably on a hard cold surface, such as the floor. Curiously, alpha activity in the electroencephalogram if present in prewithdrawal records, continues during the abstinence period in spite of manifest 'anxiety', although an increase in slow activity may be observed during abstinence following periods of addiction to other morphine-like drugs.

(b) PURPOSIVE. This group of morphine abstinence changes refers to such behavior as appears to be directed toward obtaining the drug. It is expressed verbally in terms of 'craving' and demanding drugs. Also, the subject may exhibit patterns of behavior which are highly individualized-threatening suicide, or violence, assuming bizarre postures and exaggerating his distress in dramatic ways.

"The non purposive abstinence changes reach peak intensity about 48-72 hours after abrupt withdrawal of morphine and subside gradually over a period of about one week, although some physiological variables do not return to control levels for as long as six months, while the 'purposive' abstinence changes may continue indefinitely."31 According to Lindesmith, the necessity of avoiding withdrawal distress provides the basic explanation of the nature and the processes of drug addiction. "Addiction to opiates," he points out: "... is determined by the individual's reaction to the withdrawal symptoms which occur when the drug's effects are beginning to wear off, rather than upon positive euphoric effects often erroneously attributed to its continued use. More specifically, the complex of attitudes which constitute addiction is built up in the process of conscious use of the drug to alleviate or avoid withdrawal distress. This theory, though simple in form, has considerable explanatory value, and offers a means of accounting for varied and paradoxical aspects of the habit, such as the addict's claim that he feels normal under the drug's influence, as well as his tendency to increase the dose to a point where its use becomes much more unpleasant and burdensome than it need be. The hypothesis presented makes intelligible the constant preoccupation of the addict with the drug, and explains how the unpleasant and unwelcome appellation 'dope fiend' is forced upon him."32 "Addiction occurs only when opiates are used, to alleviate withdrawal distress, after this distress has been properly understood or interpreted, that is to say, after it has been represented to the individual in terms of the linguistic symbols and cultural patterns which have grown up around the opiate habit. If the individual fails to conceive of his distress as withdrawal distress brought about by the absence of opiates he cannot become addicted, but if he does, addiction is quickly and permanently established through further use of the drug. All of the evidence unequivocally supports this conclusion. "This theory furnishes a simple but effective explanation, not only of the manner in which addiction becomes established, but also of the essential features of addiction behavior, those features which are found in addiction in all parts of the world and which are common to all cases."33 Whatever the truth of Lindesmith's theory, there can be little doubt that once a user of drugs realizes that he has become addicted his entire life becomes centered around the search for the drug. He must obtain the drug in order to be comfortable and to be able to function. He may also want the drug in order to obtain an ever elusive euphoria. The drive and compulsion for the drug is such that family, friends, property, profession may all be sacrificed to feed it. The compulsion to take the drug cannot be stopped by a threat of jail or prison sentences.