CHAPTER IV. The Mechanism of Narcotic Drug Addiction-Disease

THE MECHANISM OF NARCOTIC DRUG ADDICTION-DISEASE

I have in previous chapters referred to what are known as “withdrawal signs.” By this term has come to be known the manifestations displayed by a sufferer from addiction-disease at such times as his opiate is taken away or “withdrawn,” either totally or in part to such an extent that its amount does not meet the requirements of his physical needs.

In observing opiate addicts over a length of time no one can escape the recognition of a chain of constantly present physical manifestations inevitably following the non-administration of the drug of addiction. These may vary in priority of onset, in sequence, and in relative violence of manifestation in different cases, but they are the inevitable result of non-administration of opiate to an opiate addict. I described them as follows in a paper on “Narcotic Addiction--A Systemic Disease Condition,” which was published in the Journal of the American Medical Association, February 8, 1913. “In a general way they may be said to begin with a vague uneasiness and restlessness and sense of depression; followed by yawning, sneezing, excessive mucous secretion, sweating, nausea, uncontrolled vomiting and purging, twitching and jerking, intense cramps and pains, abdominal distress, marked circulatory and cardiac insufficiency and irregularity, pulse going from extremes of slowness to extremes of rapidity with loss of tone, facies drawn and haggard, pallor deepening to greyness, exhaustion, collapse, and in some cases death.”

These manifestations have been noted in various ways and to various extents and have been casually commented upon by most writers of the past. The conception of drug addiction as a “habit” has, however, in the past so overwhelmingly dominated the attitude of writers both medical and lay, that consideration of withdrawal signs as physical phenomena, and the analysis of their origin and mechanism on the basis of physical disease and constant body reaction has received all too little attention. The tendency has been to casually regard or belittle them as a part of the essential picture of narcotic addiction, and to place overwhelming emphasis upon mental desire as an explanation of the drug addict’s inability to discontinue the administration of opiate drugs. That these physical manifestations have had such incidental place and consideration in the general handling of the narcotic addict and in the consideration of the drug problem is to my mind the basic cause for past failure. Non-appreciation of them unquestionably explains in part the almost uniform lack of success which attended my own earliest efforts.

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 un-addicted animals gives no conception of its manifestations in the man or woman grown tolerant to its use. Many of the actions and reactions of opiate upon the un-addicted are practically lost in the addicted, and absolutely new reactions, unfound in the un-addicted individual, become the dominating factors in the opiate medication of the addict.

To some extent the fallacies connected with the general conception of narcotic addiction have arisen from the mistaken application to addicts of opiate experience, experimental or otherwise, of the non-addicted. In the matter of sensations, for example, supposed to follow opiate administration, and to the enjoyment of which is widely attributed the addict’s indulgence--in practically none of the opiate addicts, once tolerance and organic dependence are completely established, do these sensations occur. The immediate effect of opiate to the addict, depending upon the extent of tolerance, and the reaction of the patient, in dosage not too much in excess of physical body need, is apparently support to function, the restoration or maintaining of normal circulation and nerve and glandular balance, prevention or relief of the agonizing withdrawal pains and manifestations and of impending collapse.

Opiate is used by the large majority of opiate addicts simply and solely for its supportive action, and a certain amount for each addict becomes as much of a definite need and a necessary and integral part of his daily sustenance as food or air. The dream states and other sensuous results, occasionally observed, are when they occur as part of the minor toxic action of the drug, against which the developed addict is nearly or completely immune, and to the experiencing of which very few of the honest, innocent or accidental addicts have ever carried their dosage. They are commonly found only in the opium pipe smokers, an entirely different problem from that of the average narcotic addict.

As has been stated, it is a fact that for each addict, a definite amount, varying with his condition of health, elimination, physical and mental activity, etc., meets a definite body-need. On this amount he can be put and kept in good physical and mental condition under normal circumstances of environment, exertion, and general hygiene. Years of efficient activity and upright responsible lives, accomplished by well-known men and women, unsuspected addicts, bear witness to this fact. An addict neither underdosed nor overdosed practically defies detection. Less than the definite amount required for nervous and glandular and circulatory support and organic balance deprives the patient of reaction, places his vitality and energy far below par and for a long time hinders his betterment. More than this amount displays the inhibitory effects of opiates, locks up or slows secretions and body functions, and causes malnutrition, autotoxemia, autotoxicosis, and the consequent mental and physical deterioration commonly and erroneously attributed to the direct action of opiate drug.

In 1912 I wrote that so far as I knew the symptomatology attending insufficient supply of morphine (or other opiate) to an opiate addict had never received the amount of detailed study and analysis that it deserved and was not adequately interpreted. W. Marme had attributed the symptoms of morphine addiction to the toxic action of oxydimorphine. Rudolph Kobert, however, stated that Ludwig Toth subjected Marme’s claims to subsequent testing and was unable to confirm them, and that his own findings agreed with those of Toth. They found that oxydimorphine was inert by subcutaneous injection and that when thrown into the blood-stream it formed an insoluble substance causing emboli, and so producing the symptoms observed by Marme. Kobert seems to be in accord with the early findings of Magendie, that oxydimorphine is non-toxic. The experiments of Faust on dogs concerning increased power of the body to destroy morphine are well-known. It is still a matter of scientific dispute as to what extent the body of the opiate addict has developed the power to limit or destroy the poisonous properties of opiates by the conversion of these poisons through oxidation or other chemical action.

The explanation of tolerance and withdrawal phenomena on the basis of something akin to an antitoxin or antitoxic substance circulating in the blood of the addict, has also, like the oxidation explanation, been a subject of controversy. Hirschlaff claimed to have produced an antitoxic serum against morphine. Morgenroth failed to confirm Hirschlaff’s findings, and argued against the existence of an antitoxin. The animal experimental and laboratory work and findings, however, of such men as Hirschlaff, Giofreddi and Valenti have helped to influence the trend of modern thought towards what may be regarded as the present strong tendency in scientific conception of the physical mechanism of narcotic drug addiction-disease--an autogenous antidotal or antitoxic substance.

A recent paper by DuMez of the United States Public Health Service gives a comprehensive review of the work which has been done in connection with the study of increased tolerance and withdrawal phenomena, and shows conclusively the gradual inclination of modern opinion.

There is considerable literature discussing various theories and experiments and observations, which has, however, not had widespread recognition.

REFERENCES

Bishop, E. S., “Narcotic Addiction--A Systemic Disease Condition,” Journal A. M. A., Feb. 8, 1913.

Marme, W., “Untersuchungen zur acuten und chronischen Morphinvergiftung,” Deutsch. med. Wchnschr. 9: 197-198.

Kobert, R., “Lehrbuch der Intoxikationen,” Stuttgart, 2; 995, 1906.

Toth, L., “Bemerkungen zur Erklärung der chronischen Morphium Intoxikation,” Schmidt’s Jahrb. 229: 135, 1891.

Faust, E. S., “Über die Uraschen der Gewöhnung an Morphin” Arch. f. exper. Path. u. Pharmakol. 44: 217-238, 1900.

Hirschlaff, L., “Ein Heilserum zur Bekämpfung der Morphinsucht und Ähnlicher Intoxikationen,” Berl. klin. Wchnschr. 39: 1149-1152 and 1174-1177, 1902.

Gioffredi, C, “L’immunite artificielle par les alcaloides,” 28, 402-407, and 31, fasc. 3, 1897.

Valenti, A., “Experimentalle Untersuchungen über den chronischen Morphinismus; Kreislaufstörungen hervorgerufen durch das Serum morphinistscher Tiere in der Abstinenzperiode,” Arch. f. exper. Path u. Pharmakol., 75: 437-462, 1914.

DuMez, A. G., “Increased Tolerance and Withdrawal Phenomena in Chronic Morphinism, A Review of the Literature,” Jour. A. M. A., 72: 1069-1072, 1919.

My own present opinion and conception remains as expressed in a paper, “Narcotic Addiction--A Systemic Disease Condition,” written in 1912 and published in the Journal of the American Medical Association, Feb. 8, 1913, as follows, “It is my opinion that, however much increased oxidation aids in the handling of morphine, it is to the formation of an antitoxic substance that we must look for explanation of our clinical manifestations and for the classification of morphine-addiction as a definite medical entity. This opinion is based on certain clinical manifestations of morphine effect and the symptomatology attending insufficient supply of morphine to those addicted, on certain phenomena observed during and following treatment, on the persistence of tolerance and on the susceptibility of the cured patient to the re-formation of addiction.”

Before elaborating this conception of addiction-disease, I think it desirable to repeat the enumeration of the principal manifestations of “withdrawal” or body-need for opiate drug. In a general way, they may be said to begin with a vague uneasiness and restlessness and sense of depression and weakness; followed by yawning, sneezing, sweating, excessive mucous secretion, nausea, uncontrollable vomiting and purging or diarrhea, twitching and jerking, sometimes violent jactitation, intense muscular cramps and pains (described as if the flesh were being torn from the bones), abdominal pain and distress, marked cardiac and circulatory insufficiency, and irregularity (often with marked dyspnea), pulse going from extremes of slowness to extremes of rapidity, with lowered blood-pressure and loss of tone, facies drawn and haggard, pallor deepening to greyness, exhaustion, collapse and in some cases, death.

Essential Mechanism of Narcotic Drug Addiction-Disease

If such clean-cut, strikingly apparent, constant, and undeniably physical phenomena and symptomatology as I have described are to be adequately explained, there must be some physical mechanism, some definite body process working upon fundamental principles of disease reaction. They certainly are not psychiatric manifestations nor the expressions of habit, appetite, vice, nor morbid indulgence. Enjoyment of morphine for itself, even in such patients as have ever experienced such enjoyment, is lost long before the stage of rooted or completely developed addiction is reached. Physical results must be explained by physical cause.

Tolerance of and immunity to the toxic effects of narcotic drugs are primary and striking characteristics in the development of addiction. An antitoxin or antidotal substance is the recognized mechanism of their production in most diseases admittedly developing these characteristics. I have adopted the hypothesis, therefore, that an antidotal substance is manufactured by the body as a protection against the poisonous effects of narcotic drugs constantly administered. Such a substance, manufactured in the body, being antidotal to morphine, might well possess toxic properties of its own, exactly opposite in manifestation to those possessed by morphine and other opiates. Toxic substances exactly opposite to opiate in their action might readily account for the severe withdrawal signs, parallel in their extent to the extent of opiate insufficiency, and resembling in their characteristics the manifestations of acute poisoning.

A hypothetical antidotal toxic substance, manufactured by the body as a protection against the toxic effects of continued administration of an opiate drug, will therefore explain the well-known development of tolerance and immunity in these cases, and will account for the violent physical withdrawal signs. In a word, it will explain the disease fundamentals on a definite physical basis.

Such an hypothesis will explain the stages of development of addiction before outlined. In the stage of tolerance the antidotal toxic substance has begun to make its appearance in the body and to protect it against slight narcotic excess, but its manufacture is not sufficiently established to continue longer than necessary to neutralize the narcotic administered. In the stage of beginning addiction, or beginning narcotic-need, its manufacture has become more developed and more constant and proceeds for a longer time after the discontinuance of the narcotic drug. In the stage of fully developed addiction, or absolute narcotic need, the manufacture of the antidotal toxic substance has become practically an established pseudo-physiological body-process, and will continue long after the administration of the narcotic drug for reasons into which I have gone elsewhere. In other words, in narcotic drug addiction some antidotal toxic substance has become the constantly present poison, and the narcotic drug itself has become simply the antidote demanded for its control. In brief, fundamentally and basically, narcotic drug addiction is a condition presenting definite physical phenomena, symptoms, and signs, due to the presence within the body of some autogenous poison requiring narcotic drug for neutralization of it or of its effects.

This explains the phenomena of the mathematical exactness with which the minimum daily need can be estimated under experimental conditions, and with which doses less than the amount of actual body need relieve existing withdrawal signs in definite proportion to the amount of opiate administered. In exact proportion as the drug of addiction is present in the body to neutralize or oppose some antidotal poison, is the patient free from withdrawal symptoms and from physical craving for the narcotic drug.

The development and existence of such mechanism in the body of the opiate addict is suggested also by the apparent continuance of tolerance to opiate existing after long periods without drug in individuals who had previously suffered from addiction-disease, and in the susceptibility of the former sufferer subsequent to the arrest of his physical need for opiate, to the re-establishment of that need by the subsequent administration of the drug.

Illustrative of this phenomenon is a case who, after about two years of relief from addiction-disease, developed pneumonia and to whom in delirium and threatened death, opiates were administered as unavoidable medication. After cessation of his delirium, he was dismayed to discover addiction-manifestations and body-need for opiate drug had been re-established. This history is one of a number in my possession, and has been verified.

The case demonstrating the longest persistence of susceptibility among my records, is that of a man in the early fifties who underwent an emergency operation for infected gall-bladder. A day or two following operation he developed excruciating pain in his right side just under the ribs. It had been necessary to administer opiates since a day or two before the operation. I was called in consultation for the purpose of determining the character and origin of the pain, and diagnosed a pleurisy, the pain of which subsided on the following day. Opiates were discontinued with a result of precipitating unmistakable withdrawal phenomena. To his great anger and surprise, I accused the patient of being an opiate addict. He indignantly declared that he had never used opiates in his life. Subsequent investigation with the aid of older members of his family disclosed a distinct and typical history of addiction manifestations following opiate administration in the course of treatment of a complicated fracture of his thigh in early boyhood. The drug had been withdrawn at that time and the addiction manifestations finally disappeared, he never having been aware of the facts. His reawakened addiction-manifestations were easily and quickly checked.

It is evident from many histories that large dosage robbed of or modified in its toxic effect, and even in the opiate manifestations usual in subjects who have never been made tolerant, and small dosage being sufficient to re-awaken physical need for opiates are conditions which do exist and persist for indefinite periods. The resemblance between this continued tolerance and the conditions existing in diseases which confer immunity and having a generally accepted antitoxin mechanism is too close to be ignored.

Evidence of a toxic substance in the body of a narcotic-addict is further presented by the similarity of the clinical pictures presented by these cases of acute opiate need and extremely severe cases of acute poisoning from materials such as the ptomains and some other poisons. Acute opiate need is clinically typical of intense suffering and prostration from the action of some powerful poison. Its symptoms cannot be due to opiate, for the reason that the administration of opiate relieves them, and relieves them exactly in ratio to the amount of opiate administered. They can be held at any given stage by gradation of the opiate dosage. Their manifestations, moreover, are exactly opposite to opiate effect. They are to my mind best explained as due to the action of some toxic substance, antidotal to opiate, prepared by the body for its protection in response to continued opiate presence in the body, as antitoxins are prepared for the neutralization of or opposition to the organic poisons of invading bacteria. The chemical or physical character or nature of such substance has not been yet determined.

The presence of such a substance would explain the establishing of tolerance, the manifestations following opiate administration and the apparent definiteness of the amount of opiate needed. It would explain the results of under-dosage and the results of over-dosage, and the practical non-interference with function or general health when a dosage is maintained exactly sufficient in amount to neutralize the effect of some exactly antidotal body or substance.

An antidotal substance would also explain the after effects of and the so-called “relapses” which occur after most of the cases treated by whatever method or procedure, without due appreciation and proper estimation of the clinical manifestations and indications of addiction symptoms and physical body need, and without due consideration of the patient’s reactive abilities and physical condition. These patients are in a condition of restlessness, discomfort, vague pains, mental and physical depression, lowered physical vitality and weakness. They have a sense of a physical lack of support. They cannot endure nor react to over-exertion, worry, strain, etc. This condition may persist for weeks and months after no opiate has been administered. The above seem to be mild withdrawal symptoms of an incompletely arrested addiction-disease mechanism and might be explained by a continued manufacture of small amounts-of antidotal toxic substance, causing a low grade chronic poisoning. They can be duplicated in active opiate addiction before withdrawal by administering an amount of opiate slightly below the amount of need and so leaving unneutralized a small amount of the antidotal toxic substance.

If continued production of a toxic antidotal substance, after discontinuance of the drug which called it into being is to explain the existence of the condition I have just described, the causation of this continued production must be accounted for. It is conceivable that in the development of addiction-disease mechanism a tolerance of and slowness to eliminate opiate or some product of opiate is acquired by all the cells of the body, perhaps especially by the liver, and that these tolerant and atonic cells are extremely slow of opiate elimination. Under this condition, a residue of opiate or some product of opiate capable of antidotal substance stimulation might remain unresponsive, or very slow of response, to ordinary cellular and other elimination. If this should prove to be the fact, it would account for a continued production of antidotal toxic substance, and might, moreover, in any given case, either before or after cessation of opiate medication, be one of the determining factors in the amount of antidotal substance produced, or, in other words, in the measure of the extent of body-need for opiate drug.

Inhibition of Function

What characteristic action exists in opiate or narcotic drugs which gives them this power to establish the above described mechanism? It seems to me that it is, above all, their power to inhibit body function. They tend markedly to arrest metabolic processes. They inhibit glandular activity. They inhibit unstriped muscle activity and hence peristalsis. They, therefore, cause a slowing up of glandular function and intestinal activity, and of elimination. This results in an accumulation of opiate in the body. It is this constant accumulation to which the body must become tolerant by the development of some mechanism for its protection.

Autointoxication and Autotoxicosis

It is to the element of inhibition of function also that we must look for explanation of what is by far the most important element in the immediate picture presented by most individual cases. I refer to autotoxicosis and to auto- and intestinal toxemia. The same power that locks up within the body the opiate drug, locks up the toxic products of tissue activity and tissue waste, of intestinal poisons and of insufficient metabolism. Autotoxemia itself is markedly inhibitory in its action, and contributes no little to its own increase and to the further development of narcotic disease.

It is not at all impossible that any inhibiting poison constantly present in the body will some day be found to establish a mechanism of protection, similar to that of opiate addiction, and that some of the states now popularly and loosely classified under the general head of “autointoxications” will be recognized as really addiction-states, in which the body has become progressively tolerant of its own poisons. I believe that it can be demonstrated that some of the phenomena and manifestations at times observed in chronically inhibited and autotoxic individuals in whom there can be no suspicion of any opiate or narcotic element are analogous to the phenomena of narcotic addiction mechanism. It is not inconceivable that any inhibiting poison or toxin is capable of producing its own addiction-mechanism, and it has seemed to me that my own clinical familiarity with the action and reaction of narcotic, inhibiting, or addiction-forming drugs and of addiction-mechanism upon circulation, glandular and intestinal and other function has been of no little assistance in the interpretation, control and remedy of other chronic intoxications.

Upon the extent of inhibition of function and autointoxication, therefore, depend some of the immediately predominating manifestations in individual cases. They must be reckoned with and eliminated in the measure of addiction-disease in the individual sufferer. In many cases they contribute the immediate and compelling indications for rational therapeutic endeavor. To a considerable extent they determine circulatory efficiency and metabolic and glandular activity and balance. They largely control physical tone and physical reaction. Inhibition and intestinal and autotoxemia cause most of the physical and mental deterioration, and much of the incidental symptomatology so widely ascribed directly to narcotic drug effect. Upon the extent of their presence, therefore, depends greatly the clinical picture in the individual case. This doubtless accounts for the acidosis, noted by Jennings and others, inasmuch as it has been definitely proved that acidosis is commonly present in all conditions of functional depression and exhaustion.

With inhibition and auto and other toxemia eliminated or reduced to a minimum, the patient can go through many years, an apparent normal man, well-nourished, reactive, in good physical tone, mentally sane and physically competent. Under these conditions he shows practically nothing abnormal as long as he gets properly administered, his accustomed narcotic drug, in the amount of its minimum physical requirement or body-need. His condition is often unsuspected by those nearest and dearest to him, and the popularly held opinion that narcotic addiction shortens life does not seem to be upheld by the facts in his case. Such cases as his are far more numerous than has as yet been realized.

In the types of narcotic addicts most widely recognized inhibition of function and autointoxication is marked, and the opiate drug is used in excess of body-need. The addict of this description becomes a deteriorated wreck, requiring high doses of opiate for the satisfaction of abnormal body-need, mentally and physically incompetent--the generally accepted picture of the so-called “dope-fiend,” a deteriorated, degenerated, malnourished wretch, degraded, avoided and condemned.

Inhibition of function and autointoxication should not be vague terms. They cause and are measurable by definite clinical evidence. They display manifest phenomena and symptoms, and become increasingly defined material entities as the clinician looks for them as such. Much of inhibition of function and autointoxication and of their manifestations, has been recognized and taught under their own heading and in connection with conditions other than narcotic drug addiction-disease. That the influence and importance of inhibition of function and autointoxication in the development, and manifestations of the narcotic drug addict has escaped general and widespread recognition, is evidence of the small amount of unbiased clinical study, and of analytical clinical interpretation of material physical phenomena, hitherto accorded to narcotic drug cases.

I would not have it concluded that all symptoms and manifestations arising in the handling of a drug addict are due to the factors and elements I have discussed in this chapter. It must be always in the mind of the intelligent and conscientious physician, that he has in his care a human being with the same medical and psychical possibilities that must be taken into careful and complete account, as in the handling of any other sick person. There is an unfortunate tendency to overlook concurrent, or complicating or pre-existing conditions in the handling of the narcotic drug addict. These cases are often extremely complex and difficult to analyze, and for adequate comprehension and handling of them, the symptoms and manifestations they show should be appreciated in their true origin and character as they occur in each individual case.