Pathological pain differs profoundly from physiological pain. It is a psychic response to impulses originating in tissues which are abnormal either because of damage produced by external stimuli or because of inflammatory, circulatory, neoplastic, or other processes. When pain is present as a consequence of tissue damage or disease, it can no longer be considered as a warning of danger but constitutes a sign of injury.

The general response to pathological pain is totally different from the response to physiological pain. Instead of the organism being prepared for fight or flight, its efforts are directed toward placing the painful injured area, or the entire body at rest; and, to protect the painful area from further injury, the pulse rate generally slows, the blood pressure falls and often there is sweating and nausea. (10)

The local nature of the changes responsible for pathological pain has raised the problem of the several possible mechanisms of action which may intervene in inducing this pain.

1. Locally originated stimuli produced by damaged tissues themselves may act directly upon the pain end organs to induce pain impulses. Lewis has suggested that the pain associated with tissue damage is a result of the action of locally elaborated abnormal chemical substances. (10) This possibility was first considered by von Frey (11) although actually the second pain described by him was due to different rates of pain impulse transmission. Lewis (10) and his associates have studied pain in erythralgia which represents a typical form of pathological pain. (12, 13) They have shown that when skin has been injured and thus rendered hyperalgesic but not actually painful, simple arrest of circulation to this injured area may induce pain. A similar phenomenon is evident when a muscle is exercised vigorously while its circulation is arrested. If the constricting blood pressure cuff is released, the pain that is experienced during the period of ischemia disappears, but if the cuff is reinflated, pain may recur without further exercise. In both instances, no new stimulus is required to arouse pain. It has been found that in erythralgia, neither vasodilatation nor change in skin temperature is the factor responsible for lowering the pain threshold. According to Lewis, when the circulation to the affected area is severely reduced, accumulated stable chemical substances elaborated by the damaged tissues may act directly as the pain stimulus. No definite evidence has been offered by these researchers, however, as to the chemical nature of the elaborated substances involved.

2. Local changes in damaged tissues may bring about a lowering of the nerve threshold for pain. Lewis has demonstrated the spread of the lowered threshold to nerves far beyond the site of the lesion itself. He studied the cutaneous hyperalgesia following tissue damaging excitation of a tiny area of skin by a tapered forceps or faradic current. By producing damage in a previously anaesthetized area, he found that the local changes brought about by the damage did not produce hyperalgesia in the surrounding skin until the effects of the local anaesthetic wore off. The localized nerve changes then created a wide zone of hyperalgesia for prolonged periods. Tower (14) has presented evidence to show that the receptor end structures for pain have an arborizing rather than a plexiform arrangement, thus making unnecessary the postulation of an autonomically unidentified "nocifensor" nerve system, as proposed by Lewis, (15) to account for the type of spread of the hyperalgesia. The extent and especially the distribution of this area of hyperalgesia has clearly indicated that it is the result of a lowered threshold in the arborizing branches of the cutaneous nerve, a few branches of which were originally intensely stimulated. When a few fibers of a cutaneous nerve were directly stimulated, the same effect was observed. The findings suggested that a local tissue change lowers the threshold for pain for the nerve endings of the damaged area, and that this effect may spread through other branches of the cutaneous nerve involved as well as through larger nerve trunks so that the resultant area of hyperalgesia becomes very extensive.

3. Local changes may alter end organs ordinarily concerned with other forms of sensation in such a way that the impulses originated by them evoke the sensation of pain. Certain areas such as the appendix and the mucosa of the stomach apparently cannot, under normal circumstances, be incited to respond painfully to any form of stimulation. (16) However, in the presence of inflammation, the same stimuli may give rise to pain in these areas. The relationship between the end organs or nerves ordinarily concerned with the reception of other forms of sensation and those of pain has been considered by several authors. Weddell (17) has demonstrated that the various complex end organ structures are supplied with accessory fibers, unmyelinated and beaded, analogous to those considered to be pain receptors. Head (18) has shown in experiments on the glans penis that there may be a fusion of various sensations into a single concept and that one sensation may inhibit another. According to Feng, (19) the balance in excitability between touch and pain receptors may be upset peripherally by liberation of a chemical substance as the result of injury.

Considerable evidence exists to indicate that pain is the most primitive form of sensation. It is possible that in the presence of pathological disturbances, through dedifferentiation complex systems for the reception and transmission of other modalities of sensation come to act as pain receptors.

Whatever the exact mechanisms may be, the findings of different investigators have led them to the conclusion that abnormal chemical substances are released from pathologically affected tissues and that these chemical substances may play an important role in the production of pathological pain.