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.

ADDICTION TO MORPHINE

Addiction to morphine may be used as a prototype of addiction to analgesic drugs. Ordinarily, individuals with a psychologic makeup which renders them susceptible to addiction are introduced to drugs as a result of association with persons who are already addicted. Proper therapeutic administration of morphine seldom leads to addiction, except when administration is justifiably prolonged, adequate pain relief becoming more important than probable addiction. Most frequently, but not always, new addicts are recruited among members of minority groups growing up in economically depressed areas of the larger cities. In our particular culture males are more susceptible to adiction than are females. Most often addiction begins in the third decade of life but the onset may be between the ages of 15 and 20 years. Boys who are drifting into or living near the delinquent fringes of society are particularly susceptible. Ordinarily, the adolescent addict has some knowledge about drugs and about addiction before he begins their use. Experimentation with marihuana may precede experimentation with morphine or heroin. In the beginning of addiction the drug is usually taken either as a snuff (heroin) or subcutaneously (morphine). Regardless of the initial route of administration the addict usually changes to intravenous administration of the drug as addiction proceeds. Initially, the potential addict takes the drug only occasionally ("joy popping"); later he begins to use it daily and, finally, as tolerance develops, he begins to increase the dose and to shorten the interval between injections. The need to obtain more and more of the drug almost inevitably leads to delinquency, to antisocial behavior, and to illegal acts.

The symptoms of intoxication with morphine prior to the establishment of tolerance vary with the individual, the amount of the drug taken and the route of administration. In the majority of persons the first doses of morphine taken without medical need produce unpleasant symptoms such as nausea, vomiting, pallor, sweating and itching. These may deter the potential addict for a time but as he continues to experiment with the drug he comes to value these unpleasant effects, since they indicate that the drug is strong and effective. Prior to the development of tolerance the drug induces slowing of the respiratory and pulse rates, decreases body temperature and reduces blood pressure slightly. the conjunctiva are usually reddened, the eyelids droop slightly and blinking of the eyelids is less frequent. There is no nystagmus, slurring of speech or ataxia. Appetite is lessened, sexual drive is diminished and the sensation of fatigue is abolished. In the nontolerant individual morphine may induce a short period of increased psychomotor activity manifested by increased loquaciousness and a burst of ill-directed physical activity, such as mopping, sweeping, etc. If the dose is sufficiently large, increased activity is succeeded by a period of drowsiness and hypoactivity. The addict may drift into a light sleep, suddenly awaken, and then drift back to sleep. This state is termed "being on the nod" or, by the younger generation of addicts, "goofing off." It is in this peculiar state of alternating somnolence and wakefulness that opium dreams occur. The dreams are not exceptionally beautiful but are identical with fantasies in which the patient indulges when not taking morphine. The use of the drug simply facilitates indulgence in fantasy.

Intravenous use of morphine or similar substances produces dramatic physiologic and psychologic effects. Within a few seconds after an intravenous injection of morphine the addict experiences sudden dizziness; the blood vessels of the skin and mucous membranes dilate, the resultant flushing being most prominent over the upper half of the body; intense itching occurs; and a rumbling sensation is felt in the stomach, When questioned carefully most addicts will compare the effects of the intravenous administration of morphine to a sexual orgasm, except that the sensation is referred to the abdomen rather than to the genitals. When heroin, dilaudid, or methadone are used the transient dizziness is greater, and flushing, itching, and tinkling are absent. Many addicts prefer these latter drugs because of the absence of the "needles and pins" sensation. The acute effects of an intravenous injection subside within a few minutes. The symptoms thereafter are identical with those observed following subcutaneous administration.

4 Wikler, A. Recent progress in research on the neurophysiologic basis of morphine addiction. Am. J. Psychiat., 105: 329, 1948.

Symptoms during maintained addiction.-As the addict becomes tolerant the state of semisomnolence disappears, respiratory and pulse rates become normal, blood pressure is normal and temperature is usually at the upper limit of the normal range. The pupils, however, remain constricted and constipation is always present. If a sufficient supply of the drug is available, the overt behavior of the addict is not unusual and he can carry on a highly skilled, technical occupation in a fairly satisfactory manner. Emaciation, which is frequently observed, is a secondary effect and is due to the addict using most of his money for drugs rather than for food. The only signs of addiction present may be needle marks, tattooed scars over the veins and constricted pupils. If drugs are difficult to obtain and the addict cannot maintain a constant supply he will experience symptoms of abstinence, will be nervous and may be absent from work or school. Marked changes in sexual activity occur during addiction to opiates. Libido declines in both males and females so that the frequency of intercourse is greatly diminished. While the male does not become impotent, the length of intercourse necessary to obtain an orgasm is greatly increased. Women usually cease to menstruate and pregnancy is rare.

The

The morphine abstinence syndrome.-If morphine is withheld from a person who is strongly addicted to that drug, a self-limited illness appears which constitutes one of the most stereotyped syndromes in clinical medicine. During the first 12 to 14 hours of abstinence there are no obvious symptoms or signs; then occasional yawning, light perspiration, rhinorrhea and mild lacrimation are likely to appear. The addict usually goes into an abnormal tossing, restless sleep (the "yen"). After 18 to 24 hours of abstinence the patient awakens and, thereafter, has insomnia. Yawning, rhinorrhea, lacrimation and perspiration becomes much more marked; dilatation of the pupils and recurring waves of gooseflesh are seen. Twitching of various muscle groups occurs. The patient complains bitterly of severe aches in the back and legs and of hot and cold "flashes." addict usually curls up in bed, his knees drawn up to his abdomen and covers himself with as many blankets as he can find, even though the weather may be hot. He continuously twitches his feet. After about 36 hours restlessness becomes extreme; the addict moves from side to side in the bed, gets in and out of bed and is constantly in motion. Frequently this hyperactivity leads to chafing of the skin on the elbows and knees. The patient begins to retch, vomit and have diarrhea. Concomitantly, the intensity of all the other signs increases and the addict is unable to sleep. He eats and drinks very little and loses weight rapidly, sometimes as much as 10 pounds in 24 hours. He becomes disheveled, unkempt, unshaven, dirty and extremely miserable. Respiration usually increases, particularly in depth, blood pressure rises 15 to 30 mm. of Hg and body temperature is elevated about 1° C. Symptoms reach peak intensity 48 hours after the last dose of morphine is administered, remain intense until the 72d hour of abstinence and then begin to decline. After 7 to 10 days all objective signs of abstinence have disappeared, although the patient may still complain of insomnia, weakness, nervousness and muscle aches and pains for several weeks.

Like any other biologic phenomenon, the morphine abstinence syndrome varies somewhat, both qualitatively and quantitatively, in different individuals. Thus in a group of persons addicted to 240 milligrams of morphine daily, a few will show only mild abstinence symptoms following withdrawal; most will have moderately severe symptoms; and a few will be quite ill. Some patients vomit repeatedly; others never vomit.

A sufficiently large dose of morphine, or some equivalent drug, abolishes symptoms of abstinence within a very few minutes. It is a dramatic experience to observe a miserably ill person receive an intravenous injection of morphine, and to see him 30 minutes later shaved, clean, laughing, and joking. The emotional significance of this abrupt reversal of the withdrawal illness is discussed in the paper on The Psychiatric Aspects of Drug Addiction.

Within limits, the intensity of the abstinence syndrome is dependent upon the dose the individual has been receiving. The relationship of the dose to the intensity of the syndrome is, however, an exponential function, so that increasing the dose of morphine beyond 480 to 600 milligrams of morphine sulfate daily does not cause a significant increase in the severity of the abstinence syndrome.

Addiction to Other Opiates.-Addiction to all preparations containing opium, and to all the commonly used drugs that are chemically related to morphine, qualitatively resembles addiction to morphine. A high degree of tolerance can be developed to any of these substances and such differences as do exist in the rate Andrews, H. L. and Himmelsbach, C. K. Relation of the intensity of the morphine abstinence syndrome to dosage. J. Pharmacol. and Exper. Therap., 81: 228, 1944.

of development of tolerance are not of great practical significance. The chief differences in addiction to these various drugs are related to differences in potency and length of action. Heroin, metopon, and dilaudid are more potent than morphine so that, in terms of weight, the amounts taken are smaller. The length of action of these three compounds is shorter than that of morphine so that the number of doses required per day is greater. Due to the short length of action, signs of abstinence from these three drugs appear earlier, reach peak intensity sooner and decline more rapidly than signs of abstinence from morphine. The length of action of dromoran is somewhat longer than that of morphine so that withdrawal symptoms appear more slowly, are somewhat less intense and subside more slowly than the abstinence syndrome of morphine. Codeine, being far less potent than morphine, is less frequently a drug of addiction but when addiction to codeine does occur the amounts consumed may be enormous (2,400 to 3,600 milligrams daily). Signs of abstinence from codeine appear more slowly, are less intense and somewhat more prolonged than signs of abstinence from morphine. Dihydrocodeinone (hycodan) is far more potent than codeine and so is greatly preferred by addicts to codeine. The intensity and time course of the dihydrocodeinone abstinence syndrome lie between that of morphine and codeine. Since the effects of opium and of preparations containing opium are due to the morphine content of the opium, addiction to these substances does not differ significantly from addiction to morphine.

Addiction to Methadone.-Methadone is a synthetic analgesic drug which chemically is not related to morphine. The pharmacologic effects of methadone, however, closely resemble those of morphine in both animals and in man. Length of action of methadone in man is considerably longer than that of morphine so that cumulative effects appear in nontolerant individuals when several small doses are taken daily. Tolerance to methadone is less complete and develops somewhat more slowly than does tolerance to morphine. The drug may be taken orally, subcutaneously or intravenously. It is quite irritating and, if injected intravenously at frequent intervals, causes extensive phlebothrombosis. Injection of large amounts subcutaneously causes marked induration of the skin and subcutaneous tissues. Physical dependence on methadone definitely does occur. Signs of abstinence appear slowly (are usually not evident until the third or fourth day of withdrawal) and are less intense than signs of abstinence from morphine. Subjective symptoms of abstinence (weakness, fatigue, aching, and insomnia) may be present for 6 weeks following withdrawal.

Addiction to Meperidine (Demerol).-Addiction to meperidine requires special comment for two reasons: the belief that this drug is not addicting is still widespread and the incidence of addiction to meperidine among physicians and nurses is so high that one could justifiably speak of it as "the doctors' and nurses' addiction." The increase in addiction to meperidine is reflected in the admission figures of the Public Health Service Hospital at Lexington, Ky. Between July 1, 1946, and July 1, 1947, only six meperidine addicts were admitted to this institution. Between July 1, 1950, and July 1, 1951, 268 meperidine addicts entered this hospital. All of these 268 persons were regarded as "primary" meperidine addicts (persons who had not been, so far as could be ascertained from their histories, addicted to any other drug). Forty-four of the 268 meperidine addicts were physicians, 44 were nurses, and 9 were medical technicians or nurses aides.

Subjective effects induced by meperidine differ somewhat from those of morphine. The drug causes considerably more dizziness and a greater degree of elation. The length of action of meperidine is relatively short so that addicted persons ordinarily take the drug subcutaneously or intramuscularly at intervals of only 2 to 3 hours, both day and night. Since the drug is fairly irritating, marked induration of the skin and muscles occurs and large skin ulcers may be present. Human addicts develop a significant degree of tolerance and may elevate their doses to levels of 1,000 to 4,000 milligrams daily. Tolerance to the toxic effects, however, is not complete, so meperidine addicts may show twiching of the muscles, tremors, mental confusion, hallucinations, dilated pupils, dry mouth and, at times, convulsions. The electroencephalogram may be quite abnormal, showing paroxysmal bursts of slow voltage high waves and spike and dome discharges. Impairment of ability to work is far greater than in the case of addiction to morphine. Abstinence from meperidine resembles abstinence from morphine. Due to the short length of action, signs of abstinence are evident in 3 to 4 hours and

Isbell, H., Wikler, A., Eddy, N. B., Wilson, J. L. and Maron, C. F. Tolerance and addiction liability of 6-dimethylamino-4-4-diphenylheptanone-3 (methadon). J. A. M. A., 135: 888, 1947. 'Himmelsbach, C. K. Studies on the addiction liability of demerol. J. Pharmacol. and Exper. Therap., 75: 64, 1942. Andrews, H. L. Cortical effects of demerol. J. Pharmacol, and Exper. Therap., 76: 89, 1942.

reach maximum intensity 8 to 12 hours after the last dose. Thereafter, signs of abstinence decline rapidly and usually disappear completely in 4 or 5 days. At peak intensity, restlessness and nervousness are far worse than during abstinence from morphine. Twitching of muscle groups, which may become so gross as to involve entire extremities, is frequently observed. The usual autonomic signs (yawning, mydriasis, etc.) are present but are less prominent than during abstinence from morphine.

ADDICTION TO HYPNOTICS

Barbiturate addiction.-Barbiturate addiction can be used as the prototype of addiction to hypnotics. It is wise to reiterate that barbiturate addiction implies habitual consumption of amounts of barbiturates far in excess of those used therapeutically. There is no evidence that significant physical and emotional dependence occur in patients who consume only the usual therapeutic doses of these drugs. Addiction ordinarily does not occur unless the patient is consuming 0.8 gram or more of one of the potent, quickly acting barbiturates daily.

In general, the etiology of barbiturate addiction resembles that of addiction to morphine. Personality abnormalities are of prime importance, with various types of neuroses and character disorders being the most prominent diagnostic categories in this type of addiction. Addiction to alcohol or opiates is frequently involved in the genesis of barbiturate addiction. Addiction to barbiturates is frequently a mixed intoxication, with concomitant abuse of both alcohol and amphetamine being very common.

Barbiturate addicts usually take the drug orally. Occasionaly, opiate addicts may attempt to inject the contents of the capsules. Since the barbiturates are quite irritating this practice frequently leads to formation of large skin ulcers. Any of the common types of barbiturates may be used, but addicts prefer the potent, quickly acting drugs, such as pentobarbital (nembutal), secobarbital (seconal) and amobarbital (amytal) to the less potent, slowly acting preparations, such as phenobarbital and barbital. Ordinarily barbiturate addicts consume the drugs at intervals throughout the day, with the greatest quantities being ingested at night.

Intoxication with barbiturates resembles intoxication with alcohol. The symptoms include impairment of mental functioning, loss of emotional control, poor judgment, confusion, abnormal behavior of various types and, occasionally, a toxic psychosis. Objectively, nystagmus, dysarthria, ataxia in gait and station, and adiadokokinesis are prominent signs. The electroencephalogram shows a characteristic fast pattern. Coma is unusual. Respiratory rate and minute volume are not greatly depressed. Inanition is not a prominent feature of uncomplicated barbiturate addiction and, if present, suggests that the addict is also using large amounts of amphetamine or alcohol. The intensity of symptoms of intoxication varies from individual to individual and in the same individual from day to day. These variations are partly related to food intake, since the effects of the barbiturates appear sooner and are much more intense if the drug is taken into an empty stomach.

Although partial tolerance to barbiturates does develop it is never complete. Each individual has a definite limit to his tolerance and if the dose is elevated, even 0.1 gram daily above this level, the degree of intoxication markedly increases. For this reason acute poisoning may occur in a chronically intoxicated individual. Definite abstinence symptoms follow withdrawal of barbiturates. Intensity of symptoms of abstinence varies with the dose the addict has been consuming, the length of time he has been addicted, the degree of intoxication produced by the doses he was consuming, and with individual factors which are not understood. Following abrupt withdrawal of barbiturates from persons who have been consuming 0.8 gm. or more of barbiturates daily, symptoms of intoxication decline during the first 8 hours and the patient appears to improve. As the signs of intoxication decline, increasing anxiety, nervousness, headache, twitching of various muscle groups, tremor, weakness, impaired cardiovascular responses on standing and vomiting become evident. These symptoms usually become fairly intense after 16 hours and are quite severe after 24 hours of abstinence. the symptoms develop the electroencephalographic pattern shows progressive slowing. Eventually, paroxysmal bursts of high-voltage slow waves and spike and dome complexes are noted. Between the 30th and 48th hours of withdrawal convulsions of grand mal type are very likely to occur. Occasionally, seizures are observed as early as the 16th hour of abstinence and as late as the 8th day. The convulsions may be preceded or followed by bouts of uncontrollable twitching Isbell, H., Altschul, S., Kopnetsky, C. H., Eisenman, A. J., Flanary, H. G. and Fraser, H. F. Chronic barbiturate intoxication. An experimental study. Arch. Neurol and Phychiat., 64: 1, 1950.

As

of the face and in one or more extremities. In all probability these represent abortive or minor seizures. Following convulsions the patients usually are confused for a time. After an hour or two confusion lessens and some patients may recover without further incident. Others develop increasing insomnia culminating in a delirium, which is likely to begin and to be worse at night. The delirium is characterized by confusion, marked tremors, disorientation in time and place (usually not in person), hallucinations and delusions. Hallucinations are predominantly visual although auditory hallucinations do occur. The types of hallucinations which occur are extremely variable and resemble those seen in delirium tremens. The patient's reaction to the delirium varies from one of amusement at the queer people and animals he is observing to one of extreme ahitation, anxiety and frantic attempts to escape from imaginary persecutors. Agitation may lead to extreme exhaustion and even to death.10.

Like abstinence from morphine, the barbiturate abstinence syndrome is a selflimited condition and patients eventually recover (unless they incur a fatal injury during a seizure or die from exhaustion) even though no treatment is given. Ordinarily, the delirium lasts less than 5 days and ends with a prolonged period of sleep. Clinical recovery appears to be complete and no organic sequelae are known to occur.

Like all other clinical syndromes, abstinence from barbiturates varies in different individuals. Practically all patients who have been consuming large amounts of barbiturates will show anxiety, nervousness, insomnia, tremors, and an abnormal electroencephalogram; 75 percent will have at least one seizure and 60 percent will become delirious. The least common variation is the development of a delirium without a preceding convulsion.

Individuals who have been ingesting 0.6 gm. or less of barbiturates usually have only minor symptoms on withdrawal. These include nervousness, insomnia, and slight tremor. Convulsions are rare and delirium practically never occurs. Addi tion to Other Aliphatic Hypnotics.-Addiction to other aliphatic hypnotics such as chloral hydrate and paraldehyde does not constitute a significant problem in the United States. There is relatively little information concerning addiction to these drugs but the few case reports that do exist indicate that the symptomatology of intoxication and withdrawal are probably quite similar to that of addiction to the barbiturates.

Bromides. Chronic intoxication from bromides is apparently a less serious problem at the present time than it has been in the past, probably because of more stringent food and drug regulations which have required the withdrawal of proprietary mixtures containing bromides from the market, and because of the substitution of barbiturates and other drugs for bromides. The clinical picture is that of a slowly developing toxic psychosis which may or may not be accompanied by acneiform eruption. Diagnosis is usually made by finding an elevated blood bromide. A true tolerance to bromides does not occur and there are no abstinence symptoms.

Cocaine. In the United States pure addiction to cocaine is now quite rare. The drug is practically always used in conjunction with either morphine or heroin." Cocaine can be used as a snuff but addicts in the United States usually take cocaine intravenously. The subjective effects produced by intravenous administration of cocaine are very striking an ecstatic sensation of extreme physical and mental power; sensations of fatigue and hunger are abolished, and psychomotor activity is usually greatly increased. The subjective effects which the addicts value last only a few minutes. They are, however, so attractive that the addict will repeat the dose at intervals of only 10 to 15 minutes in order to recapture the tremendously pleasurable sensations. As the dose is repeated, toxic symptoms appear and increase. These symptoms are referable to stimulation of the central nervous system and to sensitization of the autonomic nervous system. The sympathomimetic signs include elevation of blood pressure, elevation of pulse rate, elevation of respiratory rate, sweating, exophthalmos and mydriasis. Signs of central stimulation include increased deep tendon reflexes, tremors, twitching of muscles, spasms of entire muscle groups and, occasionally, convulsions. A characteristic toxic psychosis, characterized by paranoid delusions, usually develops. The addict feels that people are talking about him and that he is being watched by detectives. Sensations of insects crawling on the skin are very common. Shadows, windowpanes or mirrors may be misinterpreted as being the figure of a detective who is watching the addict. When the toxic

10 Fraser, H. F., Shaver, M. R., Maxwell, E. S. and Isbell, H. Death due to withdrawal of barbiturates. Report of a case. (In preparation.)

11 Vogel, V. H., Isbell, H., and Chapman, K. W. Present status of narcotic addition. J. A. M. A., 138: 1019, 1948.