We next demonstrated the cause effect correlation between acid base changes and variations in the intensity of pain. Administration of acidifying or alkalizing substances could induce the same changes in pain intensity as those caused by spontaneous variations in the acid base balance of the body.

The relationship between acid base balance changes and pain intensity was thus investigated by administering strong acidifying and alkalizing agents to patients after the type of pain urinary pH correlation had been determined. Administered orally, strong acidifying substances, such as phosphoric acid, ammonium chloride or mono ammonium phosphate, increased the severity of pain with an acid pattern, (Fig. 14) and reduced the severity of one with an alkaline pattern. (Fig. 15) At the same time, it caused a lowering of the urine pH.

Pain with an alkaline pattern

Fig. 15. Pain with an alkaline pattern is relieved by oral administration of two doses of 1.5 cc phosphoric acid (50% sol.). Urinary pH changes reflect the systemic acidification.

Sodium bicarbonate or ammonium acetate in quantities that alkalinized the urine increased intensity of pain with an alkaline (Fig. 16) and diminished intensity of pain with an acid pattern. (Fig. 17)

These changes of the systemic acid base balance induced by administration of strong acidifying or alkalizing agents explains how similar changes, when they occur spontaneously, affect pain intensity. The effect may be to increase or decrease the intensity, depending upon the pattern of the existing pain. It is interesting to mention that similar changes of the systemic acid base balance, spontaneous or induced by the administration of acidifying or alkalizing agents, do not influence either the threshold or intensity of physiological pain. We have often utilized this response to alkalizing or acidifying substances as a method of recognizing the acid or alkaline pattern of pain. (Fig. 18 bis)

Pain with an alkaline pattern is intensified by oral administration

Fig. 16. Pain with an alkaline pattern is intensified by oral administration of 5 grams of sodium bicarbonate. Urinary pH changes reflect the systemic alkalinization.

Dualism In Local pH Measurements

Since it had been observed that a definite correlation exists between the variations in pain intensity of abnormal foci and changes in the general reaction of the body, it was desirable to ascertain what changes were taking place within the abnormal foci themselves at the same time.

Pain with an acid pattern is relieved by oral administration

Fig. 17. Pain with an acid pattern is relieved by oral administration of 5 grams of sodium bicarbonate. Urinary pH changes reflect the systemic alkalinization.

Patients with easily accessible superficial lesions, especially tumors, in which painful areas could be well localized, were employed in these experiments. The pattern of pain, acid or alkaline, was first determined in the manner previously described. Local pH determinations were then performed. Special glass electrodes * were used for this purpose and determinations were carried out employing a sensitive pH meter. The tip of the electrode was placed on the surface of the area to be tested if ulcerated, or was introduced into the tissue to be tested through a small incision. In reality this gives a measurement of the pH of the local interstitial fluid.

The response of the pain of a lesion to an agentThe response of the pain of a lesion to an agentThe response of the pain of a lesion to an agent

Fig. 18bis. The response of the pain of a lesion to an agent permits to identify the acid or alkaline pattern present. The effect of an acidifying and alkalizing agent corresponds to an increase or a decrease in pain intensity, according to the pain pattern present. First row, left side—acid pattern, right side—alkaline; second row, left side— acid, right side—alkaline; third row, right side—alkaline, left side—acid pattern.

Urine pH and local pH determinations were then performed at different times corresponding with spontaneous variations in the pain intensity experienced by the patient. Simultaneously, the pH values of normal tissue areas and, when possible, of nonpainful tumor areas were determined. Similar studies were carried out after administration of strong acidifying and alkalizing agents.

Many difficulties were encountered both in the choice of suitable clinical subjects and in techniques. Neoplasms proved to be the simplest type of painful abnormal process to employ. The neoplasm had to be located in a readily accessible region so that the electrodes could be introduced into an ulcerated area or through small incisions. The patient had to be able to very accurately localize the area of pain since considerable differences in pH values were found to exist in different parts of the same lesion. The pain had to be superficially localized because accurate determinations in the depths were not possible. Finally, the complete cooperation of the patient was essential.

The data obtained for a patient with an ulcerated, profusely draining carcinoma of the breast is recorded in Table II. Pain was most intense when the acid base balance of the blood, as reflected in the urine pH changes, was relatively most alkaline, and was less intense when the balance was more acid. The pH values of the painful areas of the tumor in this case showed considerable lability under the influence of spontaneous changes in the general acid base balance of the body, reaching a high of 8.5. At this time, the pain was very severe. The pain became unbearable following oral administration of 5 grams of sodium bicarbonate, and the pH within the same tumor area reached 8.8. The pH of the normal tissues in this case, even after the administration of strong alkalizing agents, never exceeded 7.4, while the tumor pH was never below 7.6.

Table II. Observations In A Case With Alkaline Pain Pattern

pH Normal

Treatment (oral)

Pain Intensity

pH Urine

Tissues

pH Tumor

None

5.4

7.3

7.6

Moderate

6.2

8.1

Very severe

7.1

7.4

8.5

Phosphoric acid

50%, 2 cc.

Slight

5.5

7.3

7.9

Sodium bicarbonate

5 grams

Unbearable

7.8

7.4

8.8

* Supplied by Hartman and Braun, Paris.

Table III. Observations In A Case With Acid Pain Pattern

pH TUMOR

Pain

PH

pH Normal

Painful

Nonpain-

Treatment (oral)

Intensity

Urine

Tissues

area

ful area

None

7.0

7.4

6.8

7.2

Moderate

5.8

6.3

7.1

Severe

5.3

7.3

5.8

6.9

Phosphoric acid

50%, 1.5 cc.

Unbearable

5.0

7.3

5.5

6.8

Sodium bicarbonate

5 grams

None

7.4

6.6

7.2

The findings in a case with acid pain are recorded in Table III. This patient had an extensive sarcoma of the face which was not ulcerated but involved the skin. Pain was most intense when the blood titrimetric alkalinity was relatively low and less severe when the alkalinity was higher. The pH values in the tissues of a painful area of the tumor were always more acid than the values found in another nonpainful area. The pH of the nonpainful area was slightly below that within normal tissues. Spontaneous changes in the acid base balance of the body brought about a reduction of the pH of the painful tumor area to 5.8, at which time the patient reported severe pain. The nonpainful tumor area had a pH of 6.9 at the same time. Following administration of 1.5 cc. of 50% phosphoric acid, pain became unbearable and the pH within the tumor tissues of the painful area fell at once to 5.5. At the same time, the nonpainful tumor area pH was 6.8 and the normal tissue pH was 7.3.

Similar results were obtained in other cases and led to the following conclusions: The pH values of the interstitial fluid of painful lesions studied in vivo differ from those of normal tissues, the hydrogen ion concentration being either higher or lower than that of normal tissues of the same individual. The pH of painful abnormal tissues is much more labile and extremely sensitive to general body pH changes. Spontaneous or induced variations in the acid base balance of the body produce slight changes or none at all in the pH of the interstitial fluid in normal tissues, but give rise to more pronounced changes of the pH within painful pathological tissues.

Through this research, we have thus been able to connect pathological pain to the pH of interstitial fluid of painful lesions. A further connection could be made with the richness of the interstitial fluids in potassium. In the alkaline pattern of pain, more potassium was found in the interstitial fluids. The presence in these fluids of potassium—the cation of the cyto plasma—in higher amounts than in normal conditions was seen to induce pain. The subcutaneous administration of potassium compounds was seen to be painful, while similar salts of sodium were well tolerated. As a local acidosis was found in lesions having an acid pain pattern, a local alkalosis and an increase in potassium content appeared in those with an alkaline pain pattern. The intensity of pain in this case was found to be proportionate to the degree of abnormal deviation of the local pH and to the abnormal amounts of potassium in the interstitial fluids. In addition to variations in the acid base balance of the body, variations in the amount of serum potassium appear able to alter pain intensity in cases with an alkaline pattern. This correlation is further explained below by the place of potassium in the organization.

Oxido Reduction Potential

Differences indicating the same dualism were also found in other manifestations in painful lesions. The oxido reduction potential was measured in tumors with pain. Patients chosen were those with easily accessible superficial tumors in which painful areas could be localized. Platinum needle electrodes were introduced in the painful areas through small incisions or, if the lesions were ulcerated in the lesions themselves. The measurements of the potential present were made using a Beckman pH meter. As had been the case for the pH, it appeared important that the patient be able to indicate clearly the painful areas. Because exact location of these areas in the depths was almost impossible, superficial lesions usually were chosen for these determinations. In general, in lesions with an alkaline pattern, the measurements showed high values (such as from +100 to +350 millivolts) while in lesions with pain of the acid pattern, the values were low (such as -2 to -15 millivolts).

Abnormal Substances

Changes in the local pH, like changes in acid and alkaline patterns, could be related to the appearance and subsequent accumulation of different substances in the lesion. Increased concentration of lactic acid was found in the interstitial fluids of acid pattern lesions, while increased concentrations of sodium and especially potassium ions were found in the interstitial fluid of lesions with an alkaline pattern.

Processes leading to a local acidosis are known and ascribed to the well known anoxybiotic metabolism of carbohydrates. They result from lack of the "respiratory" oxybiotic phase of carbohydrate metabolism, with the consequent conversion of pyruvic acid into lactic acid. Only part of the lactic acid is changed into glycogen through the Pasteur Myerhoff reaction, and an accumulation of lactic acid results. While the presence of lactic acid is well known, its presence has not previously been related to pain or other manifestations. We could show this correlation in some cases. (Note 3)

The scientific literature offered no information concerning the appearance of alkaline compounds. We were able to establish that the presence of sodium ions coincides with another anomaly found in these lesions—a high fixation of chlorides in the lesions themselves. Values of 1600 mgr. of CI., or even higher, per 100 gms. of wet tissue were found in these lesions instead of about 400 mgr./100 gms. measured in normal tissues. The local alkalosis and the resulting alkaline pain pattern could thus be correlated with an abnormal sodium chloride metabolism at the tissular level in which with chloride ions fixed by the cells, sodium ions remain free to combine with carbonate anions and form alkaline compounds. If the abnormal NaCl metabolism occurs in the interstitial fluid, the subsequent alkalosis induces pain. We will see later how abnormal NaCl metabolism also takes place at other levels of the organization. In these cases of alkaline pattern of pain, the fact that abnormal amounts of sodium ions still enter the cells will result in a loss by these cells of potassium which will accumulate in the pericellular fluids, and form alkaline compounds.

An immediate conclusion that could be drawn from these studies was that there is a definite dualism in pathogenesis of pain originating in abnormal tissues and that the two pain patterns evidenced in lesions with acidosis or alkalosis of the interstitial fluids indicate that processes of two opposite natures go on at the tissular level.

Other Acid And Alkaline Symptoms

Using the same method of investigation as in the study of pain, a relationship between variations in intensity of certain other symptoms and variations in urinary pH could be found. Acid and alkaline patterns of itching could be recognized. The same patterns could be found for vertigo and impaired hearing. Among psychiatric manifestations, manic depressive states showed changes that could be related to acid base variations.

The correlation between dyspnea and acid base variations was contrary to what we expected. Classically, dyspnea is believed to be associated only with an increase of acidity of blood. However, both acid and alkaline patterns of dyspnea were observed, and could be related more directly to changes at the tissue level. We will review here the pathogenesis of itching, vertigo, dyspnea, and other conditions, under this dualistic aspect.