We have observed above, dualism prevails in nature. The concept of an oscillatory dynamic balance—the result of alternate operation of opposed forces—has been of special value in the study of most of the physiological phenomena. Over the years we have also constantly observed that in most physiopathological manifestations, dualistic patterns can be recognized. This dualistic pathogenic concept has helped to guide our study of disease. In cancer, it has permitted better understanding of many processes and manifestations. It has also served as a basis for our attempts to influence cancer and other conditions therapeutically. It was in the study of pain that, initially, we found clear evidence of pathogenic dualism.

Pain

Many years ago, during experiments with an alcoholic extract of human placenta as a therapeutic agent in terminal cancer cases, a curious effect was observed. In some patients with painful lesions, administration of the preparation resulted in a decrease in the intensity of pain and even in its disappearance within a few minutes, with relief usually lasting for hours. In other cases, however, there was an opposite effect; pain increased in intensity within a few minutes after an injection. In some subjects, the exacerbation was so great and pain became so unbearable that the experimental treatment had to be discontinued quickly. In several cases in which the preparation was used in progressively larger doses, another noteworthy effect was observed: after the first injections, pain decreased and even disappeared for several days, only to have a new pain arise as treatment continued. This new pain became more intense after each injection so that the therapy had to be discontinued. Patients clearly recognized the difference between pains. The new one frequently had a burning character.

Thus, it became apparent that one substance could increase pain in some subjects and alleviate it in others, and could even alter the nature of the pain in the same subject. Pain, as demonstrated by antagonistic responses to a single agent, thus appeared to have a dual nature. Our immediate problem was to investigate this and its significance.

Physiological And Pathological Pain

In discussing the sensation of pain, most authors have found it necessary to distinguish between different types of pain. Some have classified pain as: 1) spontaneous, or 2) provoked, according to its mode of induction. Others have denned pain according to its site of origin and quality as: 1) superficial or cutaneous, and 2) deep visceral or somatic. Superficial pain from skin and mucous membranes near body orifices has been described as bright or burning in quality, while deep visceral or somatic pain arising from mesenchymal structures, certain mucous membranes and viscera has been described as diffuse and aching in quality. In many respects, attempts to define and classify pain in these terms have served to confuse rather than to clarify the problem.

That different types of pains do exist is an observation based upon common experience. For example, when a stimulus of sufficient intensity is applied to the skin for an adequate period of time, a sensation of pain is induced. This pain disappears rapidly when the stimulus is removed. But if the stimulus has been of such intensity and duration as to produce tissue damage, an after pain may recur spontaneously some time after the stimulus has ceased. The original pain serves as a warning that the tissues are endangered. The after pain, however, cannot be considered as a direct effect of the application of an external stimulus, but is rather a manifestation of true tissue damage.

As a first step, two categories of pain—one induced in normal tissue by external intervention, the other appearing as a pathological manifestation of an existing lesion—were established. We called the first, which is a normal sensorial sensation, "physiological" or "sensorial" pain. The second, a symptom of an abnormal local condition, was called "pathological" or "symptomatic" pain. This separation helped to eliminate discrepancies otherwise encountered in the study of pain, discrepancies which result when two entirely different manifestations, one sensorial and the other symptomatic, are studied under the same heading and investigated by the same methods.

Pain may be induced in damaged tissues by various stimuli not of sufficient intensity to arouse pain sensations in normal tissues. This sensitivity constitutes an abnormal response of tissues that have undergone pathological changes. Inflammatory, traumatic, circulatory, neoplastic or other pathological changes similarly may bring about either spontaneous pain or an abnormal degree of sensitivity of the involved tissues to external stimuli.

There are, therefore, two general types of pain which are biologically different. The first is a direct response of normal tissues to external stimuli which serves as a warning of danger. The organism reacts to this type of pain by seeking to run or to fight. The second type of pain arises as a consequence of tissue damage or disease to which the body responds by attempting to put the injured area at rest. This second type of pain, whether spontaneous or provoked, superficial or deep, is biologically different from the first pain experienced following the application of sufficiently intense external stimuli to normal tissues.

For purposes of further study, it would appear to be advantageous to distinguish between physiological or sensorial pain which is the response of normal tissues to noxious external stimuli, and pathological or symptomatic pain which is a manifestation of abnormal tissues. In the study of pain in all its aspects, it is necessary to keep this distinction in mind. While various investigative methods have furnished data concerning physiological pain, the information thus obtained is of very limited value when applied to the problem of pathological pain. However, it is pathological pain which constitutes the vital clinical problem, physiological pain being of concern in medicine primarily in the field of anaesthesia. (Note 1)

Dualism In Pathological Pain

It was only in pathological pain that a dual character was encountered. For one thing, it was noted that in some patients with chronic pain—associated with tumors, arthritis or other conditions—the pain intensity was not constant. In many of these patients, variations in pain intensity could be seen to follow a pattern. Although the variations usually are referred to as "spontaneous," we could show that they were related to the time of day. Furthermore, the variations were not the same for all patients. In one group, pain was severe in the morning and diminished toward evening, while in another group, little or no pain was felt in the morning and exacerbations occurred in the evening.

The intake of food also had a dual influence. In some patients with tumors far removed from the gastro intestinal tract, pain was increased by eating while in others pain decreased. Patients themselves often recognized this relationship and many whose pain was increased with the intake of food refused to eat for fear of aggravating their suffering, while those of the other group wanted to eat whenever pain was severe in order to reduce its intensity.

These observations on the influence of time of day and intake of food on pain led to the study of the acid base balance of the body since this balance is known to be influenced by the same two factors—time of day and food intake.

In a preliminary study we considered a special aspect of the acid base balance of the body, that is, the several mechanisms involved and their possible intervention in the change of pain intensity. A study was made of blood pH, titrimetric alkalinity, CO2 combining power, relative chloride distribution between erythrocytes and plasma, as well as urinary pH for the indications they furnish concerning the acid base balance. The blood is highly buffered in order to avoid damage, through abnormal pH values, to cells in general and especially to those of the nervous system. Consequently, the variations in the blood pH are as limited as possible. Alkaline reserve and the chlorides repartition represent only part systems in the general acid base balance. Titrimetric alkalinity, corresponding to the sum of ionized and nonionized constituents, furnish information of the broadest scale of the acid base balance. Consequently it appears to be a highly significant measurement. Through the non ionized constituents, it can vary greatly without influencing blood pH. It reflects thus otherwise hidden changes in the acid base balance. We could show that alone, among all the variable factors of the blood acid base balance, total titrimetric alkalinity of blood varies in parallel with the urinary pH. (Note 2)

As an immediate result of this research, it was possible to utilize the changes in the urinary pH as an indication of the most important variations occurring in the systemic acid base balance. This makes it possible to use changes in the urinary pH as an indicator of the relationship between acid base balance and variations in pain intensity.