Drug Abuse

There is but little difference of opinion among the various writers as to the symptoms which may manifest themselves during the course of chronic opium intoxication, although the cause of these symptoms, the degree of their intensity, and the constancy with which they occur are matters of dispute. Many authors claim, for instance, that in-dividuals accustomed to the use of relatively small doses, when con-tinuously supplied with their accustomed dose, do not show any group of symptoms which may be termed pathognomonic of the condition. A symptom very frequently described as indicative of opium use is the contracted pupil and yet a considerable number of writers state that this may or may not be present in individual cases at all times. The same exceptions are made in the case of other classical symptoms such as emaciation, dry skin, pale or sallow complexion, and digestive disturbances, which so frequently are given as characteristic. These symptoms in many instances, it is claimed, are evidence of the use of excessive doses rather than of the condition when smaller doses are employed and are observable, for the most part, only in advanced cases where great abuse, associated with insufficient food, the use of other drugs, or general unhygienic conditions, has been practiced.
A further difficulty in classifying symptoms occurs from the fact that what one writer describes as symptoms of intoxication another will attribute to beginning withdrawal. This is not surprising when we consider the wide difference in individual susceptibility and re-sistance as well as the marked differences in the amounts consumed daily. These differences in the ability of individuals to react and hence to obliterate what might be termed characteristic symptoms in another are just as true, apparently, in this condition as in any other toxic state and constantly must be borne in mind in an attempt to describe as characteristic any symptom-complex.
Many writers, for instance, are agreed that it would be extremely difficult, if not impossible, for even an experienced observer to diagnose a case of chronic opium intoxication in an individual in perfect "drug balance." They claim that in such cases the only certain means of arriving at a diagnosis is -the segregation of the patient, the known absence of any opium product, and the consequent development of abstinence symptoms. According to Jouet,' Charcot was the first to call attention to this point and to its utility in diagnosing the exist-ence of the condition in its earlier stages among patients who were themselves unconscious of any abnormal state but who, for therapeutic reasons, had been exposed to repeated opium-taking.
In view of this close blending of the so-called symptoms evident during the different periods and stages of this condition, it is impossible for us to treat them separately. We shall consider them, therefore, as manifestations of the condition as a whole from the time of its development until that of its complete eradication.
A review of the earlier descriptions of this condition in its various stages indicates that many symptoms have been well recognized and recorded by medical writers with but few, if any, changes for a long period of time. In order to avoid needless repetition we shall con-fine ourselves chiefly to the more recent writers whose descriptions may be considered typical of current opinion.

G. H. Smith-1842.2

Smith, in describing opium-smoking in China in a communication to Dr. J. Johnson, relates the technique' of the operation, tells some-thing of its extent, and describes in some detail the condition of cases observed under treatment. The communication was read before the Westminister Medical Society on Feb. 12, 1842, and refers to the abstinence symptoms as follows:
"If the dose be not taken at the usual time, there is great prostration, vertigo, torpor, discharge of water from the eyes, and in some an involuntary discharge of semen, even when wide awake. If the privation be complete a still more formidable train of phenomena takes place. Coldness is felt over the whole body, with aching pains in all parts. Diarrhoea occurs—the most horrid feelings of wretchedness come on; and if the poison be withheld, death terminates the victim's existence."

.I. Pereira-1872.3

"The withdrawal of morphine from those accustomed to its use leads to a train of very severe effects, the sevetity being proportional to the rapidity with which the drug is withdrawn. Prominent throughout is an almost uncontrollable craving for the drug, passing sometimes into a true mania. Besides this, the first symptoms consist in spasmodic yawning and sneezing; coryza and lachrymation; and hoarseness. The pupils dilate again. The extremities am cold, the head congested. Headache, neuralgia:, and violent pains, often in the legs. The digestion is profoundly disturbed, presenting the symptoms of a violent func-tional gastroenteritis. Insomnia is a very constant symptom; the patients are very irritable and excitable, and this condition may culminate in delirium or acute mania, often suicidal. Women often have hysteric attacks. The most dangerous phenomenon is sudden collapse, ushered in by rapid, irregular and weak pulse, cold sweat, and general prostration; and often ending fatally by heart-failure. This collapse, if severe, demands the prompt injection of a moderate dose of morphine, which generally causes the symptoms to disappear."

E. Levinstein-1877.4
Another early description of the symptomatology of chronic opium intoxication is that published in "Die Morphiumsucht" by Levinstein in 1877, though lie had, in 1875, at a meeting of the Societe des Curieux de la Nature held at Gratz in September and a month later at a meet-ing of the Berlin medical society, described the condition, and, for the first time, applied to it, as we have seen above, the term morphium-sucht. His description of the symptomatology, while not the first by any means, has become classical and is probably more extensively quoted by others writing since his day than that of any other author, possessing thus an historic importance quite aside from any other.
Levinstein subdivides this symptomatology into the manifestations of chronic morphin poisoning and those of abstinence from morphin as follows:

"I. Symptoms of Chronic Morphia Poisoning. The results arising from the abuse of morphia injections generally commence to show themselves after a period of from four to six months. There are cases, however, in which its deleterious signs only become evident after some years. The earlier or later appearance of the disorders depends upon the individual susceptibility, and not upon the larger or smaller doses of morphia administered in each case.
"Many people afflicted with morbid craving for morphia feel quite well for a certain time whilst using the narcotic; no disturbances are felt, the appetite, and even the bodily weight, remains unaltered, while others become emaciated.

Soon, however, a series of morbid appearances show themselves, originating in the cerebrospinal and sympathetic nervous system. The different organs are affected in various ways; some are not implicated at all; in others., one distinct symptom predon-iinates over others to such an extent as to be the chief cause of the patient's complaints.
"The skin often loses its turgor, its previous colour, and its natural elasticity. The subcutaneous areolar tissue melts away, although some patients, especially ladies. retain a large quantity of fat in it. The face mostly becomes pale and ash-coloured, occasionally of a dark red hue; sometimes, however, it retains its normal colour; the perspiration frequently increases to an alarming extent. Skin diseases are rarely met with. Inflammation of the sebaceous glands, such as zoster and similar eruptions, which principally affect the chin, the cheeks and the intercostal spaces, show themselves from time to time, disappearing and return-ing again, in some cases to become permanent. Abscesses and infiltrations of the skin show themselves at the places where the injections have been made, extend-ing sometimes over a large space. The patients complain of cold, and even shiverings sometimes come on.
"The eyes are often devoid of lustre, the patient's glance is weak, miserable, and shy; after administering a new injection, however, they become animated, passionate, or enthusiastic. Double vision and a diminished power of accom-modation are not rarely met with.
"The pupils are generally contracted, frequently disproportionate, rarely en-larged. The mouth is generally parched, the patients complain of being thirsty, there is nausea, vomiting, dislike for meat, and want of appetite. The tongue sometimes trembles upon being shown. The bowels are mostly confined; very rarely diarrhoea sets in. The pulse in severer cases is very small, sometimes hard, but may also be thread-like. The only other symptoms observable on the part of the circulation and respiration are dyspnoea and palpitations of the heart.
"The kidneys in severe cases secrete albumin. There is dysuria, and the quantity of urine frequently diminishes. The specific gravity of the urine is rarely very high. I have seen urines of 1,004-1,038 specific gravity, and the curious fact was that the urine of a patient possessing a high specific gravity at the first examination showed the same until the end of treatment, and vice versa. It is but natural that there should have been sorne fluctuations, accord-ing to the quantity of urine secreted daily; but they still showed the above con-ditions when compared with the average quantity. The urine of people afflicted with morbid craving for morphia will nearly always reduce an alkaline solution of sulfate of copper, not precipitating it as an oxydulate. At the same time, this urine generally turns polarised light to the left.
"On the part of the .organs of generation there is weakness, impotence, and only very rarely increased excitability.
"The menstrual discharge stops through the habitual use of morphia.
"The central nervous system will become affected in many of its functions; quarrelsomeness, want of sleep, hallucinations, changeable temper, hyperaesthesia, neuralgic complaints, paraesthesia, trembling of the hands, and increased reflex action, are the chief symptoms shown by these organs.

"II. Symptoms of Abstinence from Morphia. Although persons who stiffer from morbid craving for morphia show different symptoms, some of them begin-ning to feel the effects of the poison after using it for several months, while others enjoy comparatively good health for years together, there is no difference be-tween them as regards the consequences upon the partial or entire withdrawal of the narcotic drug.
"In this respect they are all equal. None of them have the power of satisfying their passions unpunished.
"Only a few hours have passed since using the last injection of morphia, and already the feeling of comfort brought on by the action of the drug is passing off. They are overcome by a feeling of uneasiness and restlessness; the feeling of self-consciousness and self-possession is gone, and is replaced by extreme despondency ; a slight cough gradually brings. on dyspnoea, which is increased by want of sleep and hallucinations.
"The vasomotoric system shows its weakness by abundant perspiration, by the dark colour of the face, which replaces the pale condition apparent during the first few days. Flow of blood to the head and palpitation of the heart, with a hard pulse, soon show themselves. The latter symptom often disappears sud-denly, and is replaced by a slow, irregular, threadlike pulse which is a sign of the beginning of a severe collapse. The reflex irritability increases, the patients begin to sneeze and to have paroxysms of yawning ; they start if any one ap-proaches them; touching their skin causes crampy movement or convulsions; the trembling of the hands, if not already evident, now becomes distinctly per-ceptible. The power of speech is disordered; limping and stammering takes place. Diplopia, and disorders of the power of accommodation, frequently ac-companied by increased secretion of the lachrymal glands, show themselves. The patients are overcome by a feeling of weakness and total want of energy, and are thus compelled to lie in bed.
"Neuralgic affections on various parts of the body, pain in the front and back of the head, cardialgia, abnormal sensations in the legs, associated with saliva-tion, coryza, nausea, vomiting, and diarrhoea, tend to bring them into a desper-ate condition.
"Some persons will bear up with fortitude under all these trials; they will quietly remain in bed, and will endure the unavoidable suffering, hardly uttering a complaint. Of the others, although the great minority of them sleep and doze during this trying time, some can find rest nowhere; they jump out of bed, run about the room in a state of fear, crying and shrieking. Gradually they become calmer, although occasionally their excitement increases. A state of frenzy, brought on by hallucinations and illusions of all the sensory organs, at last causes a morbid condition, to which I have given the name of Delirium Tremens, resulting from morbid craving for morphia, it being similar to that caused by alcohol. Some of the patients, however, will be found walking about in deep despair, hoping to find an opportunity of freeing themselves for ever from their condition."

"The Collapse. On the second or third day after the deprivation of morphia a state of weakness in nearly all cases will supervene, due to the small quantity of food taken, during the previous time, the diarrhoea, sleeplessness, and vomit-ing. The pulse gets small, the face becomes pale, the patient stops in bed and has the appearance of being utterly exhausted.
"This slight collapse is of no great importance, and disappears as soon as the patient commences to take food regularly, or else it turns to a severe collapse, which is fraught with danger, and requires the greatest assiduity and care on the part of the medical attendant.
"The severe collapse may begin with premonitory symptoms, very often with a change in the voice and articulation. The patients are hoarse, they stammer or lisp when talking, there is twitching in some of the muscles of the face, and the trembling of the hands, already present, increases. The collapse may also appear suddenly at a time when the severest symptoms of abstinence, such as vomiting and diarrhoea, have passed off, and when we least expect such an occurrence. The patients while sitting in bed and talking to their attendants at once become quiet, fall back on the pillow, and sink into a state of unconsciousness, which cannot at first be overcome even by the most powerful stimulants. The face sinks in and is of a deathlike color. The nose is pointed, the eyes are bright, the pulse diminishes to 40 or 44 strokes, and the patient, after experiencing a feeling of nausea and approaching death, loses consciousness. If raised up the head falls on the chest, and no loud speaking or irritation of the skin is taken notice of. This condition may last from fifteen minutes to nearly an hour; it either recurs again three or four times during the twenty-four hours at short intervals, the patient in the meantime not entirely recovering his senses; or consciousness returns at once; or, lastly as observed by Fiedler, death ensues, accompanied by symptoms of paralysis of the brain."

D. Jouet-1883.5

Jouet states in regard to symptomatology that different systems and organs are affected in different individuals. In some, the nervous system suffers first and these show cerebro-spinal symptoms, excita-bility, changes in character, hyperesthesia of special senses, or general sensitiveness. In others, the circulatory system is most affected and there occur palpitation, pre-cordial pain, etc. In still others, but less commonly, the respiratory apparatus is affected and dyspnoea, apnoea, cough, and oppression dominate the scene.
The gastro-intestinal apparatus is most often affected. Anorexia, dyspepsia, and constipation almost always accompany chronic morphinism. These are the symptoms that lead most directly to the terminal cachexia. Finally there are cases in which the genito-urinary system is profoundly affected with albuminuria, impotence, amenorrhoea, sometimes diabetes complicating seriously the ordinary phe-nomena of the intoxication.
These variations appear to constitute so many clinical varieties.
The onset of characteristic symptoms takes place some time after the first injection; the permanent changes of the organism do not de-velop for from five to seven months (Levinstein). This period is very variable in different subjects and depends more on organic conditions than on the initial doses and the rapidity of their increase.
During the entire period of invasion, of the establishment of the malady, no appreciable symptoms are seen except sometimes a slight loss of weight.

L. Guinard and F. Devay-1894.6

In experiments on a dog covering a period of seven and one-half months these authors noted, shortly after injections of 8 cg. of morphin per day were begun, activity of the salivary glands. They state that, while in man the sweat glands are stimulated in morphinism and the other secretions including the salivary secretions are diminished, in this dog hypersalivation was noted, a fact which Calvet also observed.
Vomiting, which became automatic during the early part of the experiment, ceased when large doses, 60 cg., were reached.
During the first four months, each injection plunged the the dog into a deep sleep, but this gradually became less profound, while the animal became more and more somnolent in the intervals between the in-jections. In the fourth month, when doses of 60 cg. were given, alarm-ing symptoms developed and the animal sank into a continuous torpor from which he hardly awoke for nourishment and it was necessary to return to smaller doses after about two weeks of these large doses. In the third month, sensorial troubles were noted, pupillary reflexes became less sharp, the iris remained immobile, the animal did not obey the voice and seemed completely indifferent to petting, and cir-culatory, respiratory, and thermic depression, which returned to normal on injection, were noted.
As to nutrition, while the dog ate well, nothing abnormal in digestive functions were noted, except for a little constipation during the first ten days. However, he lost in weight and about three months after the beginning injection he had lost 8 kilos. At the end of six and one-half months he had lost 2 more. His appearance was deplorable, emacia-tion was extreme and a red cell count showed only 2,300,000 per cmm. a drop of more than 2,000,000. Most authors admit that the sexual desire in man during chronic morphinism is checked, though Gartner and some others deny this. In this dog it became progressively lax and finally disappeared toward the fifth month of intoxication.
When the morphin was abruptly withdrawn, six and one-half months after the beginning of the experiment, there was evident loss of appe-tite, for two or three days, the salivation continuing for five days and then disappearing. He began to eat well, but unlike human beings, he did not regain his normal weight, remaining thin. After discontinuing the injections for about two months, daily injections of 16 cg. were begun again and resulted fatally in about two weeks. Salivation re-turned but during the first four days he did not vomit. From the fifth day to the end, he never stopped vomiting and lost weight and appetite.

William Osler-1894.7
"The symptoms at first are slight, and moderate doses may be taken for months without serious injury and without disturbance of health. There are exceptional instances in which for a period of years excessive doses have been taken without deterioration of the mental or bodily functions. As a rule the dose necessary to obtain the desired sensations has gradually to be increased. As the effects wear off the victim experiences sensations of lassitude and mental depression, accompanied often with slight nausea and epigastric distress, symptoms which are relieved by another dose of the drug. The confirmed opium-eater presents a very characteristic appearance. There is a sallowness of the complexion which is almost pathognomonic, and he becomes emaciated, gray, and prematurely aged. He is restless, irritable, and unable to remain quiet for anytime. Itching is a common symptom. The sleep is disturbed, the appetite and digestion are de-ranged, and except when directly under the influence of the drug the mental condition is one of depression. Occasionally there are profuse sweats, which may be preceded by chills. The pupils, except when under the direct influence of the drug, are dilated sometimes unequal. Persons addicted to morphia are inveterate liars, and no reliance whatever can be placed upon their statements. In many instances this is not confined to matters relating to the vice. In women the symptoms may be associated with those of pronounced hysteria and neurasthenia. The practice may be continued for an indefinite time, usually requiring increase in the dose until ultimately enormous quantities may be needed to obtain the desired effect. Finally a condition of asthenia is induced, in which the victim takes little or no food and dies from the extreme bodily debility."

P. Sollier-1894.8

Sollier compares demorphinization with the setting-up of a true experimental disease which shows a close analogy to what takes place in infectious diseases. As in the latter, the more acute the infection, the more violent the reaction of the body and the faster and more complete the elimination of the poison and also the more rapid the recovery. For this reason, Sollier prefers treatment by rapid reduction to others in that it is neither too slow to stimulate active reaction nor so abrupt as to entail unnecessary danger. A certain difference, how-ever, exists between demorphinisation and the elimination of the poison of an infectious disease and should be borne in mind in treat-ment. He says:
"While in an infectious disease, the body, attacked in the midst of health, seeks only to eliminate the poisonous principle with which it is saturated and to come out of the struggle victorious, if it is sufficiently able to resist or if the poisoning is not too intense, in morphinism, on the other hand, the body is habituated to the poison and cannot do without it, because, only by means of this poison is it able to functionate; while the phenomena of reaction are stronger in the first instance, just as the body is stronger to resist, they are also all the stronger in the second instance with a body which is weakened."
The first problem, therefore, he states, is to deternaine the degree of real resistance of the body when the artificial stimulation of the morphin has been removed. This determination is extremely delicate and should be carried out by exact methods and should include a care-ful study of the state of functional integrity of those organs which are the most indispensable to the maintenance of life and, at the same time, are most affected by the phenomena of the elimination of morphin. With this end in view, three sets of organs should be carefully examined,—the heart and circulatory apparatus, the gastro-intestinal tract, and' the urinary apparatus. The other organs, although variously affected, have relatively little importance, as none of their effects is of such a nature as to put life in danger or to prevent a cure. He continues:
"Heart and Circulatory Apparatus. Heart weakness is one of the most con-stant and serious symptoms of morphia withdrawal; this weakness is evidenced first by a slowing of the pulse, a lessening in the strength of the contractions which become irregular. The two types of irregularity which I have most frequently noted, consist of the loss of a beat in every three or four, or eight ot nine. Frequently we see along with slowing, sudden acceleration of the pulse with precordial pain.
"Syncope may take place as well as serious accidents, such as collapse. The latter has not been mentioned' often, except in abrupt withdrawal. Levinstein also advised a modified treatment for cases where collapse was feared, either on account of the weakness of the patient or because of a cardiac affection. In the method by rapid reduction, though syncope is possible but rare, collapse is very exceptional. In this connection, this method is not more dangerous than that by gradual withdrawal. The latter, as a matter of fact, does not eliminate syn-cope nor the serious accidents of abstinence. More than once I have seen proof of this in morphinists who have tried gradual withdrawal before deciding to undergo rational treatment. The heart undergoes considerable strain during the reaction of the body, set up by morphin abstinence. One appreciates, there-fore, how any lesion, whether cardiac or pulmonary, causing more work for the heart, would markedly increase accidents. We also know how common, in old morphinists, is fatty degeneration and dilation of the heart due to the effect of the morphia intoxication itself."
"Digestive apparatus. All morphinists are more or less dyspeptic. Many of them do not eat and above all do not digest without taking either before or after meals an injection of morphin. We know that morphin injected under the skin quickly makes its appearance in the stomach, the mucosa of which is stimu-lated. It stimulates, in the same way, the intestinal glands and acts particularly on the liver which is, along with the brain, one of the organs in which morphin accumulates to the greatest degree. Also, we know that the elimination of morphin, at the time of reduction, takes place through both the stomach and in-testines with great intensity through vomiting and diarrhoea. But morphin does not act on these organs only by stimulating- the functions of their glands; it increases their muscular tonicity. As soon as it is withdrawn, there is set up an atony which is sometimes very marked and which is manifested by dilatation of the stomach and of the intestines. Dilatation of the stomach is extremely com-mon, not to say constant, in morphinists. It is on this account that the too great ingestion of liquids or solids is badly borne and causes reflex phenomena of the heart and lungs which may progress to syncope. We should, therefore, determine how dilated the stomach may be, whether it still functions well and if the biliary secretion is normal, if the intestine is free before undertaking demorphinization. Although improper feeding may lead to serious consequences, at the time of withdrawal, it is however, indispensable that the patient be well fed for as Levinstein has well stated, with frequent feedings do we avoid collapse. . ."
"Urinary apparatus. Although the elimination of morphin does not occur in great degree through the kidneys, it is important to determine the state of these organs on account of the circulatory troubles which might arise as a result of their affections and hamper the heart which has none too much strength to undergo the organic reactions of withdrawal. It is known that in the case of long standing morphinism, albuminuria is found. This albuminuria disappears often and appears to be due to a simple irritation of the kidneys, which, however, may also progress to a true Bright's disease. In this last case, it is necessary to be very careful, for a rather common phenomenon at the time of suppression, while there is neither abundant sweating nor vomiting, is anuria or the retention of urine, which except in such cases as Bright's disease, is almost without importance, as it is very transitory."
*    *
"This first point established, how is elimination carried on? Morphin acts in a particular manner on glands, and it is through these, more than through the kidneys, that elimination takes place. This fact is a matter of importance, for it explains for us, on the one hand, the vomiting, the diarrhoea and the sweats which constantly occur, and on the other hand, it shows us, that far from trying to suppress these symptoms, they must be allowed to follow their course without trying for elimination by the kidneys, which would not amount to much.
"Such is also the reason why the urine of withdrawn cases ceases to show traces of morphin as soon as the injections are stopped and it is necessary that the dose reach at least 10 cg., in order that the chemical reactions, which are complicated, be revealed in the urine.
"The symptoms set up by acute, rapid elimination of morphin, are very brief, for they only last from three to five days and their intensity varies considerably according to the length and degree of the chronic intoxication.
"These symptoms, which are what we described under the name of abstinence phenomena, consist of trembling of the legs, neuralgias, pains, sweats, alter-nating dilation of the pupils, diplopia, yawning, dyspnoea, cough, pain in the region of the heart, weakness of the heart, thirst, diarrhoea, vomiting, sexual stimulation, albuminuria, vesical tenesmus, suppression of urine, etc. They are too well known for me to describe them again. What I am here studying is not morphin abstinence but demorphinization, the way in which morphin is eliminated.
"In this connection, I would call attention to the eliminatory discharges fol-lowing those which occur so intensely in the first days of suppression and which cause the phenomena of abstinence, which I have just mentioned.
"Westphal has already described, that at the end of eight or ten days, a new eliminatory discharge of morphin occurs, accompanied by symptoms analogous to those of suppression, but less intense and lasting for from twenty-four to thirty-six hours. This crisis is, in truth, very common and generally marks the beginning of convalescence; but it is not the only one. One of the characteristics of morphin elimination is that it occurs in spurts.
"These eliminatory crises are easy to recognize and patients may easily mis-take them for illness arising from some other cause. They occur abruptly and irregularly. Suddenly, in the midst of well-established convalescence, patients are taken with weakness of the legs, circulatory disturbances after a meal (torpor, congestion of the face, etc.), loss of appetite and of sleep, at the same time that the desire for morphin returns. The tongue is a little coated, and there is diarrhoea; this is accompanied, sometimes, by bilious vomiting and lasts two or three days. Then suddenly, the la.ssitude disappears, the mental depression leaves, and the appetite is better than before, sleep returns and the convalescence follows its normal course.
"These crises may be repeated several times and occur even as long as two months after suppression. It is rare, however, in such cases for them to be accompanied with physical symptoms; they resemble more the short period of stimulation followed by one of general depression. The physical symptoms may even show themselves; sometimes there are one or more attacks of bilious vomiting, sometimes they consist of cardiac phenomena. I have had a striking example of this in the case of one of my confreres, who was suddenly seized the seventeenth day after withdrawal, while his convalescence was progressing splen-didly, with an attack of morphin-epilepsy following which he remained in a state of semi-syncope for two days and nights, characterized by repeated stop-pings of his respiration and heart and a sub-delirious state. When these symp-toms disappeared, convalescence progressed with remarkable rapidity.
"Whatever the intensity of the symptoms caused by these discharges of morphin, the dangerous part is that they are always accompanied by a sudden return of morphin need and patients are never mistaken as to what they require. I have seen cases who made a definite distinction between the dis-comfort caused by a gastric disturbance and one which was due to morphin elimination, although both of these present analogous objective manifestations. Briefly, if the morphinist undergoes one of these crises when he is not under supervision, there is a good chance that he will have recourse to morphin, which he feels is alone able to relieve him. Therefore, it is necessary to recognize this need and it is only when one is experienced in the general attitude of morphinists that one can distinguish, as they do themselves, between the sim-ilar symptoms of these two conditions, although they are totally different in origin. It is distinctions of this kind that make the supervision of morphinists so difficult when treated at home, whence arise the frequent relapses which might easily be averted. What makes this supervision still more difficult is that there comes a tirne when these crises are only evidenced by a slight passing discomfort, which is unnoticed and which is always accompanied by a desire for morphin,—this is their dominating characteristic. The recognition of these crises, which I have never seen mentioned by anyone except Westphal who only speaks of the first one, is however, of capital importance, for, what-ever may be the method of suppression adopted, one may not state that a morphinist is cured as long as he is still subject to them, in a hovvever slight form.
"For how long may these eliminatory crises occur? This is a very difficult matter to state and a -very delicate one too, because, when they only appear in the form of a desite for morphin, patients hesitate to admit them. How-ever, these transient periods of morphin need reappear from time to time, according to the statements of most morphinists, for the first six months after withdrawal. They are frequently accompanied by a slight intellectual stimu-lation followed by depression. But they disappear, generally, entirely by the end of a year, provided always that the subject does well, does not become the victim of any other poisoning, is not subject to any painful affection, above all one of the same kind as that for which he formerly took morphin. In stating, therefore, that from six months to a year is the duration of complete elimination, which permits us no longer to fear relapse in old cases of mor-phinism, I believe we are within accurate limits."

James Tyson-1900.9

"The chief symptom is, of course, the craving for morphin, but it brings with it others which are more or less temporarily relieved by a dose of the drug. Among these are irresolution and /oss of self-control, and a moral obliquity similar to that induced by alcohol, especially in women, who are the most frequent subjects. Untruthfulness, especially with regard to the drug and the quantities used, is habitual. Epigastric pain or nausea, or both, are frequently complained of toward the time when another dose is due, though whether this is actual or feigned is not always easily determined. Mental depression is a more constant and characteristic symptom, associated with intense anxiety, restlessness, and a sense of impending evil, both relieved for a time by the dose. All of these symptoms are increased by a more prolonged withdrawal of the drug, when the mental depression becomes intense, sometimes impelling to suicide. So far from the usual constipating effect of morphin being produced by the drug thus used, diarrhoea is not infrequent.
"As the habit is prolonged, tremor, paresis, and more rarely ataxia are super-added, while diffuse and neuralgic pain is complained of. Sleep is irregular, digestion is bad, and appetite and nutrition fail, the pulse becomes feeble and rapid, vasomotor derangements appear, as shown by a tendency to sweating and by dilatation of the pupils. Except when under the direct influence of the drug the patient grows weak and becomes a ready victim to acute disease."

E. Viguer-1903.1°

Viguer states that when the patient is deprived of his drug he experi-ences an indefinable sensation, both psychic and physical, which is the state of need. No other intoxication gives rise to this state which is characteristic of morphinism. It comprises two elements, the one psychic, the other somatic, defined by Charcot as 'the vital need.'
Among the usual symptoms of withdrawal, which he gives in detail, the author stresses the choreic movements of the arms and legs, which, he says, never fail to appear and which were specially studied by Chareot who described their rhythm, extent, and kind.

T. C. Allbutt-1905.11

"The chief and most grievous symptom is the dangerous collapse which may follow withdrawal, and, if the withdrawal be sudden, may reach an alarming and even a fatal degree. If the drug be wholly withdrawn at the beginning, an anxious restlessness and irresistible yawnings mark the approach of the time of craving; the knee-jerks, which were deficient or even absent, become exaggerated; anesthesia gives way to hyperaesthesia; the patient begins to pace the room in a state of tremulous excitement, which becomes an agony; he springs sleepless from bed, he is shaken by rigors, sweat stands upon his skin, and saliva runs from his mouth. Feverless chills and creepiness, or sharp accesses of pyrexia often simulating ague, sheezing fits, deathly pallor, sinking, nausea and hiccup are attended or followed by vomiting and diarrhoea; the pupils widen, and are sluggish in their accommodation; speech and even gait are as if palsied; hallucinations of vision, of hearing, and even of smell, take possession of the mind, and pass into a, delirium often so violent that the cautious attendant will take care that razors and garters have been removed and the windows secured. At this stage, collapse may set in, and at any moment; the physician, with his syringe charged with a small dose of morphin—say one-tenth of the accustomed dose--must not leave the patient's side for an instant. If the state becomes really alarming, the dose must be inserted; meanwhile he will do well to keep his finger upon the patient's pulse, noting any irregularity or fall in pressure and rate; in this stage, the pulse may fall as low in number as 40 or even 30 beats to the minute."

"Collapse may come on unexpectedly, even when diarrhoea has ceased; the patient becomes faint, the face pinched, and the voice hollow; the limbs may twitch; the pulse ceases at the wrist, and the signs of consciousness fail. This threatening condition may last even for an hour, or may be repeated again and again within the day. If the ordinary cordials fail to put off the danger, the injection of a small quantity of morphin must be made, lest complete collapse set in. Fortunately this remedy never fails."

M. Maguin-1909.12

Maguin goes into considerable detail as to the withdrawal symptoms after rehearsing the usual classical symptoms during the course of taking the drug, as follows:
1. Mental State--Abstinence causes first a vague uneasiness with nervousness towards the time of the accustomed dose. The patient is restless and complains of cold, he walks about his room, throws him-self on his bed, only to get up again. Often, according to Wurtz, he has a sense of heaviness in the region of the liver. The ability to sleep disappears and insomnia becomes complete. Fortunately it lasts only for a few days. In brief, the mental symptoms of demorphinization are due to a cerebral anemia which causes an acute attack of neurasthenia for two or three days.
Aside from this the syinptoms of abstinence may be based almost entirely on three chief conditions, atony, anemia, and increase in secretions.
2. The heart becomes weak and collapse may occur. The with-drawal of the poison which is a vasodilator causes a loss of circulatory equilibrium which wears out the already tired heart. If the morphin-ism has produced, as often happens, a mild carditis, degeneration, and dilatation, serious accidents may take place and produce collapse, which is, however, rather uncommon. In the circulation, abstinence leads to vaso-constriction and the patient is cold, partly because the skin is covered with sweat.
3. In spite of the atony of the digestive tract, the hypersecretion is so great that an abundant mucous diarrhoea is caused. This diarrhoea, like the urine, the sweat, and the breath, gives rise to a strongly acrid and quite characteristic odor. Digestion is able to take place because of the large amount of gastric juice which is secreted and there is an in-crease in appetite, but after each meal a hot drink is necessary to contract the stomach. The salivary hypersecretion also aids digestion. Vomiting occurs less frequently than is stated. At all events it usually consists of mucus, rarely of food.
4. Respiration—A pulmonary anemia causes dyspnoea; the re-spiratory muscles are accustomed to little work and are atonic, having lost the habit of deep breathing. They replace the depth of the movement by an increased' number.
5. Urinary Apparatus—Polyuria appears at once. It is often very great. The author has seen it reach twelve or fifteen quarts in twenty-four hours and it is necessary to take care lest the patient become too dehydrated. Elimination takes place in spurts. In the intervals of these spurts there is a lessening of the urine and even an anuria during which the condition of the patient becomes worse. When a new eliminatory discharge takes place with an increased amount of urine the patient is relieved. It has been said that these discharges are what aggravate the condition of the patient. The author does not think this is true. The patient's condition becomes aggravated before the discharge and' the patient is perfectly well aware of his improvement as soon as the discharge begins. The organism which still contains a portion of the poison (not morphin as it will be seen that it could not be morphin), forces it out into the circulation where
the patient feels it being distributed; then elimination takes place.
6. The convulsive phenomena must be especially mentioned. As a rule they consist chiefly of yawning and sneezing, sometimes ten, fifteen or twenty times in a minute. It seems as though it were a nervous discharge because, after it, the patient is relieved. Less com-monly, delirium with convulsions occurs.
7. Photophobia occurs with an intense irritation of the retina and with weakness of the ciliary muscles and of that of the iris.

D. Morat-1911.13

Morat reports the findings of a study of the secretions and blood changes occurring during chronic intoxication, withdrawal and con-valescence, in a series of cases treated by Sollier's rapid detoxication method. His discussion of symptoms occurs in connection with the effect of the chronic use of the drug and withdrawal therefrom on the different organs and systems. The liver, he states, shows in about two-thirds of the cases of long-standing use of either morphin or heroin, which were examined, a lessened area of dullness indicating that the liver was smaller than normal. In other cases, this organ was either normal or had undergone a slight increase in volume. In these cases the patients had been using the drug for a relatively short time only, from six months to two years, and in small doses. These cases included only those who did not show in their history abuse of alcohol or other affections that would affect the liver. Whethei small or large, however, the liver was sensitive to pressure and fre-quently the patients complained of a sense of weight in this region. In some cases, hepatic colic was noted. In commenting on the gly-cosuria described by some authors, he states that, as a matter of fact, it rarely occurs. Only two were noted among the 146 cases upon which this study was based and both of these were diabetic before the beginning of their use of opium. In detoxication by the rapid method, he states that the amount of bile produced is astonishing, reaching its maximum at the time of complete withdrawal. During this time of hyperactivity the liver usually becomes tender and symp-toms of insufficiency disappear. The color of the patient improves and there is often a slight hypertrophy of the organ. The digestive tract is markedly affected by chronic intoxication, the salivary secretion is much lessened, the mouth being extremely dry. The gastric and in-testinal glands suffer no less. Hunger and thirst are diminished more and more and the need of food is not felt.
During the period of withdrawal the hypersecretion of all the di-gestive glands is carried to its maximum, salivation becomes intense and diarrhoea occurs profusely, due t,o the glandular hyperactivity which exists throughout the intestinal tract and to which is added the hyperactivity of the liver. The appetite is poor during the period of withdrawal and often the stomach will not tolerate any food at all with nausea and vomiting as prominent symptoms. In the period following withdrawal, the need of food is very rapidly experienced as is that of water.
As a general rule, there is a marked lessening of the urine during intoxication. This, Morat thinks, is largely due to the fact that the morphinist drinks little water, because, even from the time of the active purgation, the urine increases as soon as the patient is required to drink a normal quantity of liquid. In spite of the lessening of the urine, its density varies little, remaining between 1.005 and 1.030, averaging about 1.020.
It is a very common error, Morat states, to believe that morphinism causes albuminuria. Pichon, Regnier, and Sollier have already cor-rected this erroneous statement. In the 146 cases studied' only 8 were found with albuminuria. Of these, some presented definite symptoms of Bright's disease and had the albuminuria before their beginning use of the drug and, in the history of others, there were noted illnesses frequently causing renal trouble such as scarlet fever, typhoid fever, etc. It, therefore, seems that the two causes of albuminuria men-tioned by Huchard must be extremely rare; first the albuminuria of centro-bulbar origin which would be tran.sitory, second, that of cardiac origin through hypotension.
During the period of suppression the secretion of urine is much af-fected. During the first two days there is a marked oliguria. This urine is highly colored and contains much phosphates and urates which persist often until the eighth day after withdrawal and recur again from time to time during convalescence. During the first hours fol-lowing the last dose, it is rare to encounter albumen in the urine. But about the fifteenth hour generally the patient complains of a pain which becomes more and more severe in the kidney region. With the appearance of this pain, the oliguria becomes more marked and there is sometimes a complete temporary anuria lasting only a few hours. At this time the urine always contains albumen, the quantity varying from .5 to 1.5 g. per litre; but often much larger quantities are seen, in one case 30 g. per litre. This production of albumen con-sists almost entirely of serum and only lasts a few days. The kidney pain quickly subsides, the quantity of urine increases each day, and frequently there develops a true polyuria. About the eighth day after withdrawal no albumen is found.
A microscopic examination of the sediment during the period of withdrawal shows many organic elements—casts and different varieties of cells as follows:
1. The casts are granular or cellulo-granular. Hyaline or colloid casts are not found nor are blood casts. The cells found in the casts are polyhedral mononuclears which have been desquamated from the uriniferous tubes and in greater numbers irregular cells in which the protoplasm is destroyed often entirely and the nuclei of which stain with greater intensity than the nuclei of the former. These nuclei are multilobular, presenting the appearance of polynuclear cells in process of destruction.
2. The different varieties of cells scattered throughout the urine are large polyhedral vesical cells, easy to recognize; the smaller cells of the uriniferous tubules sometimes are in groups of two or three and even more with typical nuclei which stain well; finally there are smaller and irregular elements presenting often a protoplasm that is scarcely visible, nuclei deeply colored, multilobular, twisted and often torn, showing the characteristics of altered polynuclears.
Within a few days, the casts quickly disappear, then little by little, the cells, and toward the tenth day after withdrawal, it is necessary to centrifuge in order to find any organic elements.
As a general rule, the sweat glands are diminished in their activity during the chronic use of the drug. After withdrawal, they react like all other gland's with a hypersecretion. So marked is this that it was necessary, in one case, to change the night clothes five or six times each night during a period of a week. These crises end quickly but from time to time during convalescence, recurrent crises give indica-tions of this overactivity of the glands.
Although the sexual activity is inhibited, as a rule, in morphinists, the author has observed a number of cases where there was no alteration of this function. The same is true of the cessation of menstrua-tion in women; usually it is absent but not always. The return of sexual activity in these cases is given by some authors as a definite sign of cure, but this is not reliable as menstruation may return during reduction while the daily dose is still considerable. In men, at the height of the period of detoxication, the spermatozoa do not seem to be abnormal either in number or motility and, he states, he has never seen the atrophy of the glands described by Levinstein as due to the intoxication. About ten or fifteen days after withdrawal, the sexual functions return in male patients. The inhibition of these functions is part of the profound inhibition that morphin exercises over the whole organism.

F. McK. Bell-1911.14

"After about six months' use of the drug some of the characteristic symptoms develop. The memory becomes treacherous, the patient may be able to recall events which have occurred years before and yet the immediate or quite recent past remains a blank, amnesia becomes marked. During a conversation words fail to come and embarrassment and confusion ensue. Insomnia gradually be-comes more pronounced, for, contrary to what we might expect, the morphine habitue does not sleep well; the nights are spent in restless tossing about or for want of a better occupation in reading. Or if by chance he should fall asleep he is obsessed by the most frightful nightmare; grotesque and hideous objects flit before his harassed imagination, he hears gruesome sounds and starts from his clammy pillow into wakefulness--only a degree less terrible than those phan-toms of his dreams. When the morning breaks he is exhausted but sleepless, he is fatigued, stupid, and ill-humored. A feeling of despondency oppresses him and this sensation predominates throughout the day or it is replaced at times by flashes of unwonted animation superinduced by the drug—fleeting and transitory brilliancy in which the ideas are exaggerated and unnatural—a lightninglike elimination of the mind fast followed by impenetrable darkness. There is a great tendency to fall asleep during the day time and at the most unseasonable hours and occasions, as for instance in the middle of a conversation. The will-power is enfeebled, whole days are often spent in bed, the patient lacking the initiative necessary to arise and tend to pressing ditties. The sense of responsibility is obtunded, and is replaced by indifference and perfect egotism. The inability for consecutive mental work develops, and added to this we find a moral inertia; he becomes untruthful, unreliable and unethical. Criticism of all kinds is resented. His self-sufficiency recognizes no other authority. He shuns society- or acts in a strange incomprehensible manner when in company. One patient whose attention I attracted to the fact that he often left my ques-tions unanswered replied that although he heard distinctly he saw no good reason why he should use the necessary mental effort to answer them. This almost incredible indifference to opinions and feelings of others is characteristic of the disease, and the morphine habitue is bound sooner or later to become a social outcast."
"Nor do we fmd that the mental and moral health are alone in the process of degeneration; perhaps the physical health deteriorates to an even greater extent. We find in most cases fatty degeneration of the heart and liver, an antemia which soon is manifested by the ashy or leaden pallor so well known to most of us. Nutrition suffers and the patients become thin or flabby. The pupils are small and react slowly to light. There is thirst, loss of appetite, or an appetite only stimulated by an ante cibum hypodermic bf morphine.
"Systematic disorders supervene and we find tremors, gastric disorders, gen-eralized pains, cough and diarrhoea, all these symptoms being relieved by resorting to the drug. As a matter of fact all the functions of the body which normally take place in a painless manner have become so subdued by the opiat,e that when it is temporarily discontinued these physiologic actions become a source of positive discomfort, if not of actual pain."
"If the drug is suddenly withdrawn we fmd the most violent symptoms of reaction: restlessness, sleeplessness, pain, vomiting, diarrhoea, coryza, yawning, sneezing, coughing, palpitation of the heart, sweating, great prostration, dilated pupils, tremors, collapse and even death.
"If the pulse becomes weak, slow and irregular, the face pallid and shrunken, watch for collapse and administer, not strychnine or other so-called cardiac stimulants, but morphine in small doses. In these cases it acts as a much better and quicker stimulant than any other drug."

E. Kraepelin-1913.15

"Little as the symptoms of dise,ase at first strike the eye in prolonged use of morphine, the whole malady has the most serious results for those whom it attacks. So far, all we know from experiments about the psychical effect of morphine is that apparently it makes the course of thought easier, but renders the carrying-out of the impulses of volition more difficult, and so disables the will. This last effect also becomes clinically prominent in the picture of chronic morphinism. The patients become flabby, and lose their power of action, their endurance, and their pleasure in work, and are thus most severely injured in their whole activity in life. To this must be added the continual alteration between the mentally exciting effect of the individual doses of morphine and the phenomena of deprivation, which set in after a few hours, and consist of painful inward restlessness and feelings of anxiety, and also of yawning, sneezing, diarrhoea, sweating, palpitation of the heart, and many other tormenting sensa-tions, which drive the sufferer headlong to fresh use of the poison. Finally, there regularly appeans an exaggerated sensibility to all kinds of pain and mental shock, inducing the sufferers to have recourse to injections for comparatively very trivial causes. In this way, the morphine unfailingly becomes the central point of the patient's whole interest in life, to which all other considerations are subordinated, and an absolutely slavish dependence on the remedy develops, which is proof of an infirmity of the will. With this are associated sleepless-ness, defective nutrition, diminution of the physical power of resistance, and exhaustion of sexual ability."

E. S. Bishop-1913.'6

"After addiction is once established, failure to administer the drug causes a chain of definite symptoms, varying in priority of onset, in sequence and in relative violence of manifestation in different cases. In a general way, they may be said to begin with a vague uneasiness and restlessness and sense of de-pression; followed by yawning, sneezing, excessive mucous secretion, nausea, uncontrolled vomiting and purging, twitching and jerking to violent jactitation, intense muscular cramps and pains, abdominal distress, marked cardiac and circulatory insufficiency and irregularity, pulse going from extremes of slowness to extremes of rapidity with loss of tone, facies drawn and haggard, pallor deep-ening to grayness, exhaustion, collapse and, in some cases, death."
Elsewhere he reminds us that:
"One of the obstacles to an appreciation of narcotic drug addiction-disease has been the casual assumption on the part of the average person, both lay and scientific, that opiate drugs act upon the addict, and that he reacts to them similarly to the actions and reactions in the non-addicted individual. Morphine action, however, as commonly observed following therapeutic administration or in experimentation upon unaddicted animals gives no conception of its mani-festations in the man or woman grown tolerant to its use. Many of the actions and reactions of opiate upon the unaddicted are practically lost in the addicted, and absolutely new reactions, unfound in the unaddicted individual, become the dominating factors in the opiate medication of the addict."

G. E. Pettey-1913.17

Pettey describes the effect of opium in delaying secretion and excre-tion and its role in the consequent storing up of toxic products as follows:
"These waste products play a much more important role in causing the diffi-cult complications met upon the withdrawal of morphine, known as abstinence symptoms, than does the drug itself. After the use of the drug is kept up for a time, upon examination of the patient, we find the skin dry and crusty, the tongue coated, breath foul, bowels habitually constipated, digestion impaired, heart action defective, and other evidences of portal engorgement. -

"When the administration of the drug is discontinued and the patient is allowed to go for a time without it, some of these symptoms give way to others of a different character, while others of them are merely intensified, but not changed in character. The dry skin gives way to excessive sweating, the constipation to diarrhoea, Colic, nausea, and other evidence of gastro-intes-tinal disorder. With this clinical picture before us, we could arrive at no other conclusion but that the patient's system was intensely saturated with toxins of intestinal and auto-origin."
"Among the early symptoms incident to the withdrawal is a slight rising of temperature and as the hours following the withdrawal of the drug pass this temperature rise increases, and if left uncorttrolled will run to very high degrees."
"From a grosser anatomical standpoint, no structural lesions result from the prolonged -use of opiates, but a careful physical examination reveals unmistakable evidence of the most widespread functional derangements; the blood is thin and deficient in the oxygen-carrying red corpuscles; the mucous membranes are pale,—in fact, all the structures show signs of profound anemia; the abdomen is full and unduly indurated; the liver is enlarged and the portal systena en-gorged; tongue coated; breath foul; skin alternately dry or excessively active, but always swarthy and yellow; heart action variable, depending upon the stage of narcotic impression; nervous reflexes either blasted or exaggerated; the muscles are flabby and relaxed; the memory is impaired; mind inactive, and the entire bearing of the patient is one of dejection and hopelessness. To sum up, the evidence clearly indicated a condition of intense intoxication with profound anemia, attended by derangement of the nervous system and im-paired mentality."
The author speculates as to the cause of the fever that accompanies withdrawal as follows:
"Another symptom which is unavoidable is a slight rise of temperature, especially during the afterpoon of each day. The author has taken much pains to determine the cause of that symptom, but is uncertain yet as to which of three or four factors is most potent in its causation. This fever appears in practically every case and continues sometimes as long as four weeks after the entire withdrawal of the drug.
"In the opinion of the author any one of several conditions that are evi-dently present. might account for the fever. We have just seen that the condi-tion of the nervous system is one of general hyperesthesia. In this condition, it is likely that the heat-centers are so disturbed that there is a loss of balance between the rate of heat production and heat radiation, thus allowing an expres-sion of hyperpyrexia.
"Then, again, the nervous system, in fact the whole organism, has become accustomed to doing its work under the restraint of the opiate. This restraint being withdrawn, it is likely that all the vital functions would be carried on at a more active rate than normal, the nerve-centers being hypersensitive. This would doubtless lead to the greater than normal production of heat.
"Again the system is usually anemic and there is a great demand for nourish-ment. This being taken. there is increased activity of the digestive process. The increased oxidation incident to this increased metabolism involves increased heat production. If the nerve-centers are disturbed so that the radiation of heat is imperfectly adjusted to heat production, it is evident that there would be hyperpyrexia from more active metabolism.
"But more likely than either of these is that there remains a residue of toxic matter in the system—in the ultimate cell—which the most persistent and thorough elimination cannot remove at once, and that the fever is due to the effects of this remnant of toxic matter upon the hypersensitive nervous system.
"While the bowel may have been thoroughly emptied and the kidneys and skin made to do their full duty, or even more, it would be practically impos-sible to perfectly cleanse the system of such an accumulation of toxic matter in a few days, or even a week or more time. Therefore, it is probable that there would remain stored away in the tissues in the very structure of the cells a residue of toxic matter, and that this would act as an exciting cause o'f the fever.
"The nerve centers, being hypersensitive, would respond with undue activity to this toxic matter.
"Then, again with this hypersensitive state of the nerve-centers the slightest absorption of toxin from the intestines would result in an acute intestinal toxemia which would be attended by some fever, and this doubtless is its source in some cases.
"But, whatever may be the correct explanation of its cause, it is present and when left uncontrolled greatly increases the discomfort of the patient during convalescence. The more perfectly the system has been cleaned of toxic matter, the less fever will follow the withdrawal of the drug and the less pain there will be during the period of convalescence. Therefore, the author is inclined to be satisfied with the idea that this fever is of toxic origin."

A. Valenti-1914.18

Valenti, 1914, in reports on a series of experiments dealing with disturbances of the circulation brought about by the injection of the serum taken from morphinized dogs in normal animals, states that when morphin is withdrawn from morphinized dogs acute disturbances of the circulation are observed, severe arrhythmia, intense acceleration of the pulse, and violent fluctuation in blood pressure. These dis-turbances subside when morphin is again given and disappear entirely as the usual daily dose is reached.

A. Lambert-1914-1924.1° 2°

Considering the symptoms, memory is one of the faculties first affected and the amnesia is similar to the beginning senile dementia. Names are the first to go ; the morphinist will relate occurrences early in his life, but will forget what he had done during the past week. He will forget the familiar names of streets, the details of his profession; thus the physician forgets the dosage of medicines and the scientific terms with which he is familiar. Amnesia of the well-marked stage of morphine intoxication is only equalled by the amnesia of paresis. The will power is enfeebled and the patients spend days in bed without sleeping and without stupor; their minds are perfectly clear but their power to do is gone. In some patients this is continuous and permanent ; in others it seems to run in crises, lasting over two or three days. Tirere is psychic asthenia. The sense of responsibility is wiped out and is replaced by the indifference of perfect egotism. Their character is modified and they are discontented grumblers, obstinately 'ugly,' ofter given to explosions of intense rage, quarreling without cause, and even destructive and dangerous to those with whom they come in contact. Often the morphinists are individuals of more than average ability and intelli-gence, realizing fully their condition, and appreciating their progressive degenera-tion. It is for this reason that they resent criticism and accept reproaches about their habit with bad grace, because they are already filled with remorse. Morphinists usually lie about their addiction because in the early stages they feel that others consider it a vice and a disgrace, however innocently it may have been acquired, and they have enough moral sense left to endeavor to hide it. If, however, they have just taken their morphine or are assured a sufficient dosage to keep them comfortable, they do not necessarily lie about other matters. The fear of being deprived of their drug is an ever-present horror. Patients have come under the writer's notice who were literally starving to death and yet have had means kept to procure the necessary amount of morphine to prevent them going through the horrors of forced withdrawal without assistance. When the craving for the drug is upon them, there is nothing to which they will not stoop to obtain it. Lying, thieving, begging in the street, prostitution itself, are to them all justifiable means to obtain the drug.
"Morphinists do not sleep well; they are subject to nocturnal hallucinations which render their nights times of terror; thus they endeavor to keep themselves awake by reading, and during the daytime are prone to fall asleep whenever they remain quiet, sitting in a chair, no matter in what place or company. The hallucinations of sight are always terrifying, and contrary to the hallucinations of alcohol, those of morphinism are not occupation deliriums. The hallucinations of sight are the most frequent; next those of hearing; those of taste and smell are rare, and those of general sensibility are exceptional, which last is always contrary to what occurs in alcoholism. The sense of taste is often dulled and sometimes even abolished. Reading and writing become impossible because pages appear clouded and deformed, and when the endeavor is made to fix a page, it dances or trembles or approaches or retrogrades, and this, together with a frequent distinct photophobia, causes great distress. Ophthalmoscopic examination does not reveal any distinct lesion. There is at times con-traction, and at times dilatation of the pupils; an anemia of the retina has been described. The visual disturbances disappear when the morphine is permanently withdrawn. The reflexes are very variable. Disturbances of the general sensi-bility are often marked and vary greatly; there are often paresthesias and sometimes intense neuralgic pain. Others show marked anesthesia, which may be confined to one side of the body. More often there is hyperesthesia, and the sole of the foot becomes so painful, that, when it is touched to the floor, it gives a sensation of burning, and the patient can only walk with short, jumping steps. Rodet considers this form of hyperesthesia as very characteristic of chronic morphinism. The tactile sensibility is usually diminished or abolished. The question often arises whether indulgence in morphine impels the individual to suicide. At times when, inadvertently, too large a dose is taken, the patient succumbs, but as long as he can obtain his drug, he is an individual without will, apathetic, and incapable of making sufficient exertion to commit suicide; if, however, the morphine be withdrawn or he cannot obtain it, the condition entirely changes.
"Troubles of digestion are common; in the early stages there is nausea, vom-iting and anorexia, which do not persist for a very long time. There is often an intense thirst; the breath is very offensive and of a peculiar odor, often spoken of as being so characteristic as to designate the morphinists by those who are brought in contact with many of these patients. They are markedly constipated and this often alternates with attacks of diarrhoea; their stools are bloody and, during the period of constipation, may be as infrequent as once or twice a month. The teeth are subject to caries, which attacks first the molars on their grinding surfaces; this extends to bicuspids, then to incisors, and last of all to the canines. This is always painless, not accompanied by any periostitis, and usually progresses with great rapidity. It usually coincides with the falling out of the hair. The disturbances of nutrition appear in some patients after a few months and in others not until after some years. Emaciation is perhaps the most striking and may go on to an extreme degree. Their faces become livid and often sallow, the expression set and there are premature wrinkles, which, with the faded sallow look of the skin, often gives a look of premature old age. The tissues lose their vitality, which accounts in a measure for the ease with which slight bruises cause ecchymosis, and the greater liability to the occurrences of abscesses.
"The pulse of the chronic morphinist is slow and there is a fall in arterial tension with, in the last stages, distinct enfeeblement of the heart action and diminution in the force. The number of respirations is slowed and, at times, they are shorter so that every now and then a long deep inspiration seems neces-sary to give the required amount of air. Dyspnoea on exertion, even if the slightest kind, is quite common. In the beginning of morphine addiction there is polyuria, which later is followed by a diminution of secretion below the normal. In many there is albuminuria which is ascribed by Levenstein to a special action of morphine on the medulla, to changes in the arterial pressure, or to a paralysis of the nerves which enter the kidney around the renal artery.

The effects in the genito-urinary system are much the same as those described under opium.
"Most women become sterile, but in spite of the cessation of menstruation, conception may take place. Pregnancy may run its normal course, or the mor-phine may cause a miscarriage 'or premature birth. Children born of morphinist mothers may be well formed and normally healthy. Often t,he children of mor-phinist parents are idiotic or show a lack of mental and physical developtnent."
"The symptoms of abstinence and the sudden cessation of opium smoking are the same in most respects as follow the withdrawal of others forms of opium, but the smoker often suffers less severely and for a shorter time. The respim-tory tract and the eyes are affected out of proportion to the rest of the body. The first symptoms are gaping, yawning, sneezing, profuse discharge of tears and MUCUS from the eyes and nose, irregularity of the pupils, ringing in the ears, followed by extreme restlessness, intense pain in the joints, nausea, vomiting and purging. A peculiar dull, drawing, dry and burning ache in the pharynx and larynx occurs, which is followed by distressing pains in the muscles, espe-cially in the calves of the legs and between the shoulders. Chills, followed by flashes of heat are felt along the spine and are followed by profuse perspiration. In some cases, if no opiate is used, the vomiting and diarrhoea continue and the restlessness and flushed face give place to complete relaxation, a ghastly pallor with sunken eye, collapse, and death; but in less severe cases or when proper remedies are used, the distressing or dangerous symptoms cease one by one. Sleeplessness persists for a long time; the bronchitis and catarrhal inflam-mations of the throat usually last for months; the pains in the legs and body gmdually disappear; the sexual power returns; the appetite gradually improves and becomes ravenous; an increase in the weight is manifested ; a return to natural buoyancy of mind begins, and the patient regains his health and strength."
"When morphine is cut off abruptly there is gieat danger of collapse. This may supervene on the second or third day, and the patient shows increased weakness, appears pinched and haggard, while the pulse becomes small and then disappears. Or he may show a sudden high pulse tension, feebleness of the heart action and suddenly, while wandering about restlessly, fall pulseless to the floor. Sometimes the fatal collapse may occur without warning while the patient is quiet. Still another form of collapse may occur; the face becomes deep red, the eyes shine brilliantly, the pulse falls to forty and the patient loses consciousness after a feeling of intense agony. These collapses may last for fifteen or twenty minutes; they may recur three or four times in the twenty-four hours and the patient may recover or die in any of them unless morphine be given. Fortunately these attacks are rare when the drug is with-drawn gradually but they are fairly common when this is done abruptly. There are some few cases on record in which the fatal collapse occurred some time after the patient was convalescent and apparently well on the road to recovery. During their periods of suffering, the patients are apt to be afflicted with dis-tressing insomnia, and, if they sleep, it is only in fitful dozes. In a longer or shorter time the suffering gmdually subsides and the patient can rest with some degree of comfort; the morbid craving has gone; the appetite returns and often becomes excessive; in women menstruation is reestablished at first painfully, later normally. In both sexes the sexual desire returns, often painfully and excessively and then subsidies. The patient goes into a rapid convalescence. When morphine is broken off, if it has been taken to quiet, some neuralgia or to benumb some unbearable sensation, these pains, although quiescent during the period of the addiction, may return in full force when the habit is broken."

Further, in Nelson's Loose-Leaf Medicine, 1920, he states:

"Those who see chiefly heroin addicts sometimes have doubts about the sudden collapse from morphin. Before heroin was used, however, it was realized that the sudden withdrawal of morphin sometinies brought about collapse and that death might ensue; in fact, this was not an infrequent occurrence. The depriva-tion of the heroin addict does not produce this same collapse. With the old-fashioned method of depriving a patient completely in two or three days, there was always the danger of a vasomotor and cardiac collapse in which the pulse would suddenly disappear; or the patient might show a sudden high tension and fulness of the pulse and suddenly while wandering about restlessly, fall pulseless to the floor."

A. Church and F. Peterson-1914.2' Church and Peterson list the symptoms as follows:

"1. Anorexia and constipation (later, diarrhoea often).
2. Cachectic anemia.
3. Cardiac weakness and intermittence and bradycardia.
4. Muscular weakness with tremor.
5. Miosis in the early stages, mydriasis later, with sluggish reaction of the pupils.
6. Impotence. Amenorrhoea in women.
7. The knee-jerks are often absent.
8. Diminished sensibility to touch and pain, and concentric limitation of the visual field.
9. Headaches and localized shooting pains, neuralgia, and paresthesias.
10. Sensation of feeling cold."
The psychic symptoms may be summarized briefly as:
"1. Siniple elementary illusions and hallucinations, muscae volitantes, tinnitus aurium.
2. Loss of will and esthetic sense, irritability; moral perversion, as in alcoholic psychic degeneration, but with little failure of memory.
3. Diminished attention, incoherence of ideas, and easily fatigued intellectual powers. A well-developed psychosis is usually the result of abstinence from morphin, and not of the chronic misuse of it. It varies in degree up to a type approaching acute mania."

J. Rogues de Fursac and A. J. Rosanoff-1916.22

"According to Chambard four periods may be distinguished in the career of a morphinomaniac, which succeed each other by imperceptible transitions.
"First period: initiation or euphoria.—It has been aptly called the honey-moon of the morphinomaniac. Under the influence of the morphine physical pains, if they exist, disappear or become abated, the organic functions become more active and the mind lapses into a pleasant reverie; ideas form themselves without any effort and combine 'to form ingenious conceptions, elaborate reso-lutions, vast projects which, alas, are never likely to last through the day,' depressing thoughts disappear and life assumes a smiling aspect."
*
"Second period: hesitation—Many subjects, conscious of their danger, make efforts to escape from it. They diminish the doses, reduce the number of injections, etc. Some even completely discontinue the use of the drug perma-nently or temporarily.
"The period of hesitation is not constantly present; many patients by reason of their ignorance or lack of determination pass directly from the first period to the third.
"Third period: morphinomania proper.—The poison has now impressed its stamp upon the organism and has established certain permanent symptoms. Moreover, its suppression gives rise to a series of characteristic phenomena, the symptoms of abstinence.
"(A) Permanent symptoms.—(a) Psychic phenotnena.—These consist in a gen-eral weakening of psychic activity, and are manifested in the intellectual sphere by sluggishness of association and impairment of attention contrasting with intact orientation and perfect lucidity, and by retrograde amnesia of reproduc-tion; representations are in some way inhibited but not destroyed.
"In the emotional sphere there are indifference and atrophy of the moral sense. All the aspirations of the patient reduce themselves to a single idea, that of procuring morphine by any possible means; disregard for conventionalities, swindling, falsehoods, violence, all seem to him permissible. Many morphino-maniacs obtain their morphine from the druggist on false prescriptions, others sell their household articles to purchase morphine for the money.
"In the sphere of the reactions there is always very marked aboulia. The patient is conscious of the ruinous results of his inactivity, but has not the power to overcome it. This symptom appears early and together with the indif-ference forms a characteristic feature of the mental state in morphinomania.
"(b) Physical symptoms.—The general nutrition always suffers: loss of flesh, pallor of the skin, etc.
"The circulatory apparatus shows general atony. The cardiac impulse is weak; the peripheral circulation is sluggish; there are transient oedemas.
"The temperature is often subnormal. A case of morphine fever has, however, been reported. (Levinstein.)
"Motility: general muscular asthenia; a tendency to fatigue; tremors; 'slow, regular oscillations resulting from a twisting movement of the limb upon itself.'"
"Sensibility: slight hyperaesthesia which is at times unilateral; diminution of the acuteness of vision, often dependent upon 'pallor of the optic disc, which may advance to atrophy.'"
"The pupils are frequently myotic.
"The tendon reflexes are occasionally diminished.
"(B) Symptoms of abstinence.—When the hour for his injection has passed the morphinomaniac becomes restless, his expression becomes anxious and his respirations accelerated. A state of anxiety soon appears, accompanied by a very marked inhibition of all the psychic functions. The patient abandons his unfinished work or conversation and leaves, complaining that he is unable to bear the tortures of which he is a victim. At the same time there is the appear-ance of the pathognomonic somatic symptoms: extreme pallor of the face, acceleration and weakening of the pulse, general prostration, cold sweats, and spells of yawning. If abstinence continues the condition may become alarming: obstinate diarrhoea appears and collapse is threatened.
"No matter how grave the symptoms become an injection of morphine always affords instantaneous relief.
"Occasionally the mental symptoms present all the features of a veritable acute psychosis: agitation, anxiety, persecutory ideas, psycho-sensory disorders, excite-ment simulating that of mania; these may be associated with hysteriform or epileptiform attacks.
"Fourth period: cachexia.—The symptoms of the preceding period become more marked. The psychic disaggregation in some cases resembles true de-mentia. The craving for the drug is greater than ever. Loss of flesh reduces the patient almost to a skeleton; the stomach rejects all food and a permanent and intractable diarrhoea sets in; the blood pressure becomes low, the cardiac impulse grows weaker and weaker, the pulse becomes small, thready and irregu-lar; renal changes, which are frequent, give rise to albuminuria.
"Numerous complications are apt to appear, rendering the prognosis still more serious; pulmonary tuberculosis, furunculosis, phlegmons hasten the fatal termi-nation, which occurs at the end of the fourth period."

J. McIver and G. E. Price--1916.25

These authors state that most of their observations of symptoms were confined to those following withdrawal of the drug, as treatment was instituted promptly on admission of the patient.
"Those were observed to some extent in every case and we will here merely enumerate the various symptoms presented: yawning, sneezing, and lacrimation, early and later insomnia, nervousness, restlessness, anorexia, nausea, vomiting, pain in the abdomen and lower extremities, diarrhoea, profuse perspiration, tachycardia, nocturnal emissions, marked asthenia, weak pulse and collapse. There was no rise of temperature except with complications. In a few cases the temperature was subnormal."

F. jC. Dercum-1917.2°

"Restlessness may become very marked and is always accompanied by a more or less marked insomnia. The patient is apt also to yawn or to sneeze a great deal. Often he complains of having caught cold, or perhaps he has an attack of difficult respiration simulating asthma. At times all the symptoms of a frank attack of cold in the head or a troublesome cough make their appear-ance. In addition, the patient complains of a sense of oppression, is distressed and frightened, becomes fault-finding and resistant and declares himself dissatis-fied with the treatment.
"The restlessness may become extreme; involuntary movements of the legs and arms make their appearance, the limbs being thrown about the bed; at other times distinct involuntary jerkings and tremor make their appearance. Sometimes there is palpitation of the heart or a sense of fluttering in the pre-cordia. Vesical tenesmus also may be noted.
"If the patient has been in the habit of taking large amounts of morphin daily and the withdrawal has been abrupt and complete, a sense of great weak-ness and fatigue supervenes; the patient is soon unable to stand or to walk. He trembles from exhaustion and his body becomes bathed in sweat. There is a profound sense of sinking in the epigastrium and very frequently gastric and abdominal pains make their appearance. Soon nausea, vomiting and profuse diarrhoea set in, the heart's action becomes weak, the pulse rapid, the extremi-ties cold. In severe cases, or if the symptoms be not relieved by a temporary recourse to the drug, the patient may become greatly agitated or disturbed, moans or cries out or may become confused and delirious."

A. R. Cushny-1918.27

"In the beginning the quantity used is small, but as tolerance is attained, ever larger quantities are required to produce any effect, until as De Quincey states in his "Confessions of an Opium-eater," 320 grains of opium may be requiied to stay the craving. The effects are generally described as stimulant, but it seems possible that they consist rather in depression of the sensibility by which the unfortunate patient becomes unconscious of the miseries of his condition, and may accordingly be able to perform his duties and maintain appearance better than when deprived of the poison. The symptoms of the opium habit are exceedingly indefinite, and the diagnosis is often almost impossible. The state-ments of the patient ought not to be taken into consideration, because these unfortunates seem to have lost all idea of honor and truthfulness. As a general rule they are nervous, weak in character and wanting in energy, and utterly unfit for work unless when supplied with the drug. The pupils are often con-tracted, the heart sometimes irregular, and tremors and unsteadiness in walking may be apparent. The appetite is bad and a considerable loss in weight occurs, and the movements of the bowels are irregular, constipation alternating with diarrhoea. Eventually melancholia and dementia may follow the prolonged use of opium, and especially of morphine. Some continue the habit for many years, however, and it would seem with comparative immunity."

W. A. White-1918.28

"The physical symptoms of prolonged use of opium in any of its forms are anorexia, irregular action of bowels, constipation alternating with diarrhoea, cardiac weakness, general muscular weakness and tremor, miosis and sluggish pupils, impotence, amenorrhoea, diminished sensibility, paresthesias, sensation of coldness."
"Mentally there is a gradual degradation. The memory and power of atten-tion become impaired and the capacity for initiation is lost. There is marked impairment in the ethical feelings and previously honest, persons will begin by lying out of business engagements and about the taking of the drug and end by associating with the most degraded persons and resorting to any means whatever, even criminal, to obtain the drug.
"Some persons who have taken opium in some form for a considerable time and in large doses develop an hallucinated state that may be of paranoid coloring or may be distinctly delirioid. Thus one patient (laudanum and whiskey) on admission to the hospital said that her food was poisoned. Another patient (morphine) is restless and excited, has hallucinations of hearing and carries on conversation with imaginary persons. Sometimes her language is vio-lent and abusive, she threatens her imaginary persecutors and will jump out of bed and run through the hallway looking for the people she thinks are after her.
"Opium has much less tendency to produce tissue degeneration than alcohol and many persons continue for years to take small doses with little apparent harm."
"Symptoms of abstinence, if they appear, are referable to the heart, stomach, bowels and nervous system; they are circulatory failure, respiratory disturbance, pyrosis, vomiting, diarrhoea, tremor, general debility, an hallucinatory delirium and sometimes profound collapse.
"If the mental and physical symptoms become grave morphine should be given and will usually relieve them. The evening dose should be omitted last, to combat any tendency t,o insomnia, and full feeding, massage and hydrotherapy are valuable adjuncts."

W. M. Kraus-1918.29

Kraus states that the withdrawal symptoms are to be encountered not only during withdrawal, but also during the intoxication itself. Every injection acts very naturally, but for a definite period, the length of which depends upon the dose. If this action commences to cease or stops entirely, due to the failure to make another injection, withdrawal symptoms will appear. Failure to appreciate this, he says, has retarded our understanding of morphin as a habit-forming drug. He states:
"The explanation of this sudden reverSal of symptoms lies in the fact that morphine taken as a habit-forming drug upsets the normal equilibrium between the sympathetic and the autonomic systems, establishing a new one. When this new equilibrium is destroyed by taking away the drug, symptoms naturally result.
"A description of the withdrawal symptoms warrants a classification. The words withdrawal symptoms imply that the symptoms are due to the absence of morphin, that this absence is the primary cause. Since this is not the entire truth, the symptoms of withdrawal have been divided into two general classes:
Class A.--Symptoms referable to the effects of morphine.
Class B.--Symptoms referable to conditions existing before the onset of the habit.
(1) Physical    (2) Psychical
"Class A.—These symptoms are the opposite to those produced by morphine. The muscular elements of the eye become very active. The pupil dilates. Its reactions are very labile. Accommodation paresis is common and troublesome. Diplopia occurs sometimes.
"The lachrymal gland becomes very active. The conjunctival sac becomes moist and tears are often the result.
"The nasal secretions are increased. Coryza is frequent. Sneezing, due in part to increased reactivity of the nervous system, in part to local irritation of secretions, is one of the first symptoms, one of no mean diagnostic value in an attempt to discover the presence of a habit by withdrawal.
"Asthma is often complained of. That is, a bronchospasm. A 'cold' appears in some, a mild bronchitis, due to hypersecretion of the bronchial epithelial glands, not at all like the dry hacking cough occasionally found in the habitue.
"The rate of respiration increases on withdrawal.
"Symptoms referable to the heart are the most dangerous. They are best considered with those referable to changes in blood-pressure. The heart-rate is increased, the pulse may become very rapid, thready, a sign of impending collapse. The blood-pressure falls, due to cardiac collapse.
"Salivation is one of the first symptoms of withdrawal.
"The hypoacidity of the habit reverses itself. Hyperacidity takes its place. This formed the basis of Hitzig's method of withdrawal. By giving alkalies, Erlenmeyer modified the gastric lavage used by Hitzig. Erlenmeyer's experience with this method, lasting over twenty years, has been most gratifying. Diar-rhoea is prevented, and the visceral symptoms in general are almost nil.
"Besides hyperacidity, nausea and vomiting are frequent, due to the labile and overactive nervous system.
"The chronic constipation of the habit changes to a profuse diarrhoea. Colicky pains may accompany this.
"Profuse sweating is one of the first signs of withdrawal and stands as a con-trast to the dry skin of the habitue. In the first paper we used this faot as a proof t,hat morphine depresses the sweat-apparatus. Those who have seen the dry skin of the habitue and the sweating of withdrawal will realize their relation. Vasodilation accounts for the mild perspiration produced occasionally by mor-phine in therapeutic or slightly larger doses.
"The cramps in the extremities are among the most distressing of withdrawal symptoms. They are due to a vasoconstriction and recall the cramps produced in some individuals by very cold water. Adrenalin was tried in a few cases, and, as was to be expected, increased the suffering. The beneficial effect, on the other hand, of hot baths is well known. Nitrates are also of great benefit.
"The menses are almost always absent during the entire period of chronic morphine poisoning, excepting a short time at the beginning of the habit. How-ever, in spite of this amenorrhoea, pregnancy may occur, showing that the ovary, as far as the follicular apparatus goes, is still functioning. The explana-tion for this is not readily obtained, for the many aspects of the relations of the ovary to menstruation are as yet unsettled. After a cure, the menses return. The first few menstrual flows are usually excessive in amount and duration.
"With the exception of a primary euphoria, those addicted to morphine have little or no sexual interest (in the narrower sense of the word). After with-drawal this usually returns, and with great intensity.
"There is, as a rule, an absence of spermatogenesis during morphine addiction. This disappears on withdrawal.
"During chronic morphinism the power of erection is often lost. Upon with-drawal it usually returns. Nocturnal pollutions may occur.
"In chronic morphinism, there are a number of symptoms suggestive of chronic hypothyroidism : dry skin, trophic changes in the nails, teeth and hair. Besides this there are the entire group of vegetative nervous system symptoms, which may form a part of hypothyroid states. Gottlieb showed that thyroid-fed rats had a diminished tolerance to morphine, while thyroidectromized rats showed an increased tolerance. From this we could say that ruts tolerated morphine in proportion to the degree of hypothyroidism. If this is proved by further work, it will be of great value in determining the best dose of morphine in dysthyroidism. Furthermore, if morphine is tolerated better by thyroidecto-mized rats, it would seem but natural that as a tolerance to morphine is obtained, a concomitant hypothyroidism should result. The evidence of the physical findings in chronic morphinism points to a depressor effect upon thyroid activity. The thyroid is the familiar accelerator of metabolism and the vegeta-tive nervous system. Thus there is depression of an accelerator function.
"Since there are vegetative nerves to the thyroid, it is probable that any effect produced results from changes' in their activity. Morphine has no action upon gland tissue.
"The symptoms which have been described are all attributable to the lack of the effect of morphine upon the organism—more particularly upon the vege-tative nervous system. They are clearly the opposite to those produced by morphine, and thus serve as a further proof of the effects of its action."

W. Hale White-1924.3°

"The symptoms are that the patient loses all sense of right and wrong, he will lie and thieve in the most degrading way, especially if his desire is to obtain the drug, and absolutely no statement that he makes can be trusted. He neglects his work, and lets his business go to ruin. He wastes and becomes anaemic, he suffers from loss of appetite, indigestion, dry mouth, sluggish bowels, and a foul tongue. The nails are brittle, the skin dry, the hair turns grey early, and falls out. There is sexual impotence, no erections take place, no semen is secreted; there is amenorrhoea, and the flow of milk is stopped, but there is polyuria. The pupils are small, and loss of muscular power, slight ataxy and tremor are present in severe cases. The arms or other parts are scarred with marks of the syringe, and 20 grains of morphine a day are sometimes taken."

O. H. Plant and I. H. Pierce-1928.3'

In the first of a series of three articles on chronic morphin poisoning after a brief review of the meager accounts available in the literature of the symptomatology of chronic morphin poisoning and withdrawal in animals, the authors state that the recording of their observations appeared to them valuable, first, "because niany observers have noted marked variations in symptoms in individual animals and if these variations are better known they may lielp to account for the widely differing theories as to the cause of morphin tolerance and of with-drawal symptoms;" and second, for the reason that "such observations would make possible a more complete comparison between chronic inorphinism and withdrawal in dogs and the corresponding clinical conditions in human subjects." Their data relate to twenty-six addic-tions with twenty-two withdrawals on eighteen dogs, some of which were re-addicted once or twice. The period of addiction of their animals varied from forty-nine to three hundred thirty days and with-drawals were made at levels of dosage ranging from thirty to two hundred thirty ingm. per kgin. of morphin sulphate.
After describing the selection of animals, the control period of obser-vation, the diet, exercise and hygiene, they state that observations were made regularly at two hour intervals during the day between 7:30 a.m. and 5:00 p.m. and occasionally between 8:00 and 12:00 p.m., beginning four weeks before the administration of morphin and continuing through the period of addiction and withdrawal, the tem-perament and behavior of the animals, as well as their physical state being noted. Morphin sulphate was employed throughout, injected subcutaneously in ten per cent. solutions. For the most part the drug was given in single daily doses at about 9:00 a.m. In some cases multiple doses were used.
The observations recorded included changes in weight, vomiting, salivation, narcosis, constipation, general behavior, appetite, parturi-tion during addiction, hypersensitiveness and skin rashes, and con-vulsions and muscular rigidity during addiction.
In all cases but one withdrawal of the drug was abrupt. As to the severity of symptoms the authors state:
"In one dog small doses of morphine were administered on the second, third and fourth days of the withdrawal period.
"Of the 22 withdrawals in which we have studied symptoms and behavior, 2 animals showed very marked symptoms (one died); 8 showed marked symptoms; 6 moderately severe symptoms, while in 6 the symptoms were slight. In the latter group while no marked disturbances were observed there were always sufficient symptoms to easily distinguish them from normal animals.
"Symptoms as a rule began on the second day of withdrawal ; they were most severe during the first week but in some instances continued for 8 to 12 days.
"There was no distinct relationship between the size of the dose at with-drawal and the severity of the symptoms although the two animals that showed very marked symptoms were withdrawn at a low dosage level (30 and 40 mgm. per kgm.). On the other hand, half of the animals that showed marked symptoms were withdrawn at a dosage of more than 100 mgm. per kgm. The three animals that were withdrawn at high dosage (200 mgm. per kgm. or over) showed only slight symptoms."

The following observed symptoms were then recorded in detail: tremors, twitching and rigidity in voluntary muscles; groaning, howl-ing and whining; restlessness; gnawing at objects within reach; change in temperament and behavior; hiccough; photophobia; salivation; vomiting; muscular weakness; respiratory distress and panting; tem-perature; sleepiness; diarrhea; and loss in weight.
In general the authors state:
"The symptoms of withdrawal after a second or third addiction did not differ in character from those observed after first addiction. The individual animals reacted in the same way each time they were withdrawn, but in three of them the symptoms were more severe during the second withdrawal ; in these three animals the period of addiction was shorter and the dose much smaller than at first withdrawal. (CDA 10, 12 and 13). In one animal that was addicted and withdrawn three times (CDA 7) the symptoms during withdrawal were never marked, although it was twice withdrawn at high dosage level (210 and 230 mgm. per kgm.) and once at a low dose (50 mgm. per kgm.). In the first experiment with this animal the addiction was developed slowly and covered a long period (330 days), in the second it was developed rapidly (83 days), while in the third the period of addiction was short (58 days) but the dose at withdrawal was relatively small.
"Our observations seem to indicate, therefore, that the marked variations which we encountered in severity of withdrawal symptoms are due to differences in the individual dogs; that they are not dependent on size of the dose or length of addiction.
"The period of addiction in dogs has given a picture that follows fairly closely the descriptions of addiction in man if one excludes certain mental or psychic changes which obviously cannot be determined in dogs. Many of the symptoms which we observed have been noted in human addicts: marked differences in individuals, vomiting, constipation, hypersensitiveness, scratching (rashes), change in temperament (irritability), and decrease in narcotic action of the drug. We realize that even our longest experiment is much shorter than the usual case of human addiction; that the poisoning was more rapidly produced and the dosage much greater than would be possible in man. It is possible that the similarity between human and canine addiction would be greater if, in the latter, the drug was administered in smaller amounts and over greater periods of time (years instead of months).
"The similarity between withdrawal symptoms in our dogs and those described in man is much closer than during addiction.' While it is true that very few of our animals gave a complete picture of the usual symptoms observed in human addicts after abrupt withdrawal, yet together they form a composite picture that includes practically all of the human symptoms that could be distinguished in an animal. One dog in particular showed symptoms that were very similar to those of abrupt withdrawal in human addicts. For this reason we give below a more detailed protocol of this animal:

"CDA 13. Female Boston bulldog. Second addiction. Withdrawal at 30 mgm. per kgm. after 70 days addiction.
"First day. Salivation as usual in the morning; somewhat brighter and more responsive. About 4 p.m. became very restless, moved about in the metabolism cage continuously. Very marked tremors in muscles of hind legs and head. Whined and groaned at times.
"Second day. 9.30 a. m. Howling, barking, and groaning. Extreme tremor and jerkiness all over her body, legs stiff, belly retracted and hard; very restless, moving stiffly from side to side of cage and often bumping it. Tremors and stiffness very near spasms but animal stays on her feet most of the time. Respiration short, jerky and noisy; mouth open but tongue not hanging out. Very thirsty, drinks water frequently. Rectal temperature 103° F. (Day before withdrawal it was 101.6° F.). Vomited twice.
"9.35 a. m. Morphine sulphate, 30 mgm. (about one-sixth of former dose). Within 20 minutes all symptoms had disappeared; no tremors, no rigidity, breathing slow and regular, no narcosis; active and friendly and shows interest in other dogs and appears normal in every way.
"4 p. m. Quiet and dozing, easily aroused but growls when disturbed (had never been cross before).
"Third day. 9 a. m. Very noisy, barking and howling; tremors very marked, legs twitching and jerking. Moves about continuously. Marked respiratory distress. When prone on floor her head is drawn back, legs stiff. Very thirsty. Friendly. Seems actually to beg for a dose. 11.00 a. m. Condition is worse. Howling continuously. Tremors are very marked. Condition very much like parathyroid tetany except that animal is more restless. Drew blood for calcium determination. When taken from cage and placed on table for injection she immediately became quiet. Received 20 mgm. morphine sulphate (one-tenth usual dose). Within a few minutes all symptoms disappeared. Was quiet, friendly, and to all appearances normal. 4.30 p. m. Is again somewhat restless and cross. No tremors or respiratory distress. Liquid stool.
"Fourth day. 11.30 a. m. Noisy, restless, raging and howling like a wild animal. Tremors and twiching as marked as yesterday; marked dyspnoea. Friendly and begging to be taken out of cage. Salivation is quite marked. Liquid stool. Vomited. When placed on table for obtaining blood sample she became quiet but was noisy and restless when returned to cage. An injection of 0.5 cc. distilled water produced quiet for about 2 minutes then symptoms returned and were as severe as ever.
11.50 a. m. 10 mgm. morphine sulphate (one-twentieth of usual dose) caused complete disappearance of all symptoms within 15 minutes and changed her from a wild raging animal into an apparently normal dog. Remained quiet for several hours.
5.00 p. m. Somewhat restless but not noisy ; slight tremors can be felt. Friendly.
"Fifth day. Very restless and noisy; tremors are still marked but none of symptoms as severe as yesterday. Diarrhea. Sleeps a little. Dyspnoea not marked. No morphine.
"Sixth to Twelfth day. Tremors and rigidity gradually diminished; slept for longer periods and howling was less persistent.
"Thirteenth to Twentieth day. Improved rapidly. Showed marked weakness and sleeps most of the time.
"The symptoms in this animal were more severe than in any other with-drawal, except in the dog that died on the third day, and were more marked than in her first withdrawal at a higher dose (160 mgm. per kgm.) and longer addiction (161 days). Figures for blood calcium in this dog fell within the normal variations.
"Another animal (CDA 11) was re-addicted to the same dose and for the same period as the one described above, and was withdrawn at the same time; it showed only moderately severe symptoms.
"Symptoms and behavior are recorded in twenty-four addictions to morphine and in twenty-two withdrawals in dogs, in which detailed observations were made over periods covering from 49 to 330 days and with doses of 30 to 230 mgm. per. kgm.
"Considerable variability in symtoms during chronic poisoning with morphine was observed.
"The severity of withdrawal symptoms varied markedly in different dogs. These differences are not related to length of addiction or size of dose at with-drawal. Two dogs showed very severe symptoms during withdrawal and in both of these the dose was relatively small. Two animals died in addiction during administration of large doses. One died on the third day of withdrawal.
"When the symtoms observed in this group of dogs are considered as a whole they form a composite picture that is strikingly similar to that obtained in chronic morphine poisoning in man; this is particularly true of withdrawal symptoms.
"We believe that the observations reported in this paper show there is marked similarity between morphine addiction and withdrawal in man and in dogs; that this similarity makes the dog a particularly suitable test object for the study of many phases of the morphine problem; that results obtained in experiments on dogs can be applied to the problems of morphine addiction with greater validity than those on any other laboratory animal."
One of the dogs died on the fourth day of withdrawal. The with-drawal symptoms in this animal had been especially severe. On the afternoon of the third day there were short periods of unconsciousness when animal failed to respond although restless and howling. Marked respiratory distress. Tremors and twitching looked like parathyroid tetany. No actual convulsions were observed. The animal died dur-ing the night and the post mortem examination indicated that con-vulsions occurred before death.
In two tables are shown the details of variations in weight during addiction and withdrawal, and a summary of the symptoms of all the animals used together with the breed, length of addiction and dose at withdrawal.

 

1 Jouet, D.—Etude stir le morphinisme chronique. These de Paris. 1883.

2 Smith, G. H.—On Opium Smoking among the Chinese. Communication to Dr. J. Johnson. Lancet. 1841-2. Vol. I. p. 707.

3 Pereira, J.—Elements of Materia Medica and Therapeutics. 1872.

4 Levinstein, E.—Die Morphittmsucht. Translated by Charles Harrer. 1878.

5 Jouet, D.—Etude sur le morphinisme chronique. These de Paris. 1883.

6 Guinard, L. and F. Devay.—Observation d'un cas de Morphinisme c.hronique chez un Chien. J. de Med. vet. et Zootech. 1894. XIX. pp. 261-269.

7 Osler, W.—The principles and practice of Medicine. 1894.

8 Sollier, P.—La Demorphinisation et le Traitement rationel de la Morphino-manie. Semaine Med. 1894. pp. 146-152.

9 ' Tyson, J.—Practice of Medicine. 1900.

10 Viguer, E.—Contribution a PEtude de la Demorphinisation. 1903.

11 Allbutt, T. C.—A System of Medicine. 1905.

12 Maguin, M.—Morphinomanie et Morphinisme. L'Echo Med. Aug. 1, 8, 15, 1909. Vol. XIII.

13 Morat, D.—Le Sang et les Secretions au cours de la Morphinomanie et de la Desintoxication. These de Paris. 1911.

14 Bell, F. McK.—Morphinisin and Morphinomania. New York Med. Jour. 1911. Vol. 93. pp. 680-682.

15 Kraepelin, E.—Lectures on Clinical Psychiatry. Authorized translation from the 2nd German ed., revised and edited by Thomas Johnstone. 1913.

16 Bishop, E S.—Narcotic Addiction—A Systemic Disease Condition, J. A. M. A. Feb. 8, 1913. Vol. LX. pp. 431-434.

17 Pettey, G. E.--Nareotie Drug Diseases and Allied Ailments. 1913.

18 Valenti, A.—Experimentelle Untersuchungen uber den chronischen Mor-phinismus; Kreislaufstorungen hervorgerufen durch das Serum morphinistischer Tiere in der Abstinenzperiode. Arch. f. exp. Path. u. Pharm. 1914. Vol. 75. pp. 437-462.

19 Lambert, A.—Chapter in Osler and McCrae's Modern Medicine. 1914. " Lambert, A.—Chapter in Nelson's Loose-leaf Medicine. 1920.

20 Church, A. and F. Peterson—Nervous and Mental Diseases. 1914.

21 Rogues de Fursac J., and A. J. Rosanoff—Manual of Psychiatry. 1916.

22 Jouet. Quoted by Chambard. loc. cit.

23 Pichon. Le morphinisme. 1890.

25 McIver, J. and G. E. Price—Drug Addiction, Analysis of one hundred and forty-seven Cases in the Philadelphia General Hospital. J. A. M. A. Feb. 12, 1916.

26 Dercum, F. X.—Relative Frequency of Drug Addiction among Middle and Upper Classes; Treatment and final Results. Penn. Med. Jour. Feb. 1917.

27 Cushny, A. R.—Pharmacology and Therapeutics or the Action of Drugs-- 1918.

28 White, W. A.—Outlines of Psychiatry-1918.

29 Kraus, W. M.—An Analysis of the Action of Morphine upon the Vegetative Nervous System of Man. Jour. of Nervous and Mental Diseases. July 1918. Vol. 48. No. 1.

30 White, W. Hale--Materia Medica, Pharmacy, Pharmacology and Thera-peutics. 1924.

31 Plant, O. H. and Pierce, I. H.—Studies in chronic morphine poisoning in dogs. I. General symptoms and behavior dining addiction and withdrawal.

Through the courtesy of the authors and of the editor of the American Journal of Pharmacology, in which this article will appear, we have been enabled to publish the abstracts and quotations included in this volume.

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