It is a subjective experience with two complementary aspects.
An aspect is a localized sensation in a particular part of the body; the other is an unpleasant quality of varying severity commonly associated with behaviors aimed at alleviating or ending the experience.
Pain has a lot in common with other sensory modalities. First, there are specific pain receptors. These are nerve endings present in most tissues in the body that only respond to harmful or potentially harmful stimuli.
Second, the messages initiated by these noxious stimuli are transmitted by specific and identified nerves to the spinal cord.
The sensitive nerve ends in tissue, and the nerve attached to it forms a primary afferent nociceptors unit. The primary afferent nociceptor contacts second-order pain-transmitting neurons in the spinal cord.
Second-order cells carry the message through well-defined pathways to higher centers, including the brainstem’s reticular formation, the thalamus, the somatosensory cortex, and the limbic system. The processes underlying pain perception are believed to involve the thalamus and cortex primarily.
Research on pain’s basic mechanisms is an increasingly exciting and promising area.
However, most of what is known about the anatomy and physiology of pain comes from studies of experimentally induced cutaneous (skin) pain. In contrast, the majority of clinical pain arises from deep tissues.
Therefore, although experimental studies provide pretty good models for acute pain, they are poor models for clinical chronic pain syndromes.
They provide little information about the muscles, joints, and tendons most often affected by chronically painful conditions. They fail to address the wide range of psychosocial factors that profoundly influence the experience of pain.
To improve our understanding and treatment of pain, we will need better animal models of human pain and better tools for studying clinical pain.
There are four main processes: transduction, transmission, modulation, and perception. Transduction refers to the processes by which tissue-damaging stimuli activate nerve endings.
Transmission refers to the relay functions using which the message is transmitted from the site of tissue injury to the brain regions underlying perception.
Modulation is a recently discovered neural process that acts specifically to reduce activity in the transmission system.
Perception is the subjective awareness produced by sensory signals; it involves the integration of many sensory messages into a coherent and meaningful whole. Perception is a complex function of various processes, including attention, expectations, and interpretation.
Transduction, transmission, and modulation are neural processes that can be studied objectively using direct observation methods.
In contrast, although there is a fundamental neural basis for it, pain awareness is a perception and therefore subjective, so it cannot be directly and objectively measured.
Even if we could measure the activity of pain-transmitting neurons in another person, to conclude that that person is in pain would require an inference based on indirect evidence.
Three stimuli can activate pain receptors in peripheral tissues: mechanical (pressure, pinch), heat, and chemical. Mechanical and heat stimuli are usually brief, while chemical stimuli are long-lasting.
Nothing is known about how these stimuli activate nociceptors. Nociceptive nerve endings are so small and scattered that they are challenging to find, let alone study.
However, some studies have been conducted on the effects of chemicals on the firing rate of identified primary afferent nociceptors. A variety of pain-producing chemicals activate or sensitize primary afferent nociceptors.
Some of them, such as potassium, histamine, and serotonin, can be released by cells in damaged tissues or by circulating blood cells that migrate from blood vessels to the area of tissue damage.
Other chemicals, such as bradykinin, prostaglandins, and leukotrienes, are synthesized by enzymes activated by tissue damage. These pain-causing chemicals are found in increasing concentrations in regions of inflammation and pain.
The transduction process involves many chemical processes that probably work together to activate the primary afferent nociceptor.
In theory, any of these substances could be measured to estimate the peripheral stimulus for pain. In practice, such trials are not available to physicians.
It should be noted that most of our knowledge of primary afferent nociceptors is derived from studies of the cutaneous nerves.
Although this work is of general importance, most clinically significant pain is generated by musculoskeletal or deep visceral tissue processes.
Scientists are beginning to study the stimuli that activate nociceptors in these deep tissues. Primary afferent nociceptors respond to pressure, muscle contraction, and irritating chemicals in the muscle.
Muscle contraction under ischemic conditions is a potent stimulus for some of these nociceptors.
Despite advances in our understanding of the physiology of musculoskeletal nociceptors, we still know very little about the mechanisms underlying common clinical problems, such as low back pain.
Even when degeneration of the spine and compression of a nerve root, a condition generally recognized as extremely painful, we do not know which nociceptors are activated or how they are activated. We also do not know what the process that leads to pain is about.
Peripheral nervous system
The nociceptive message is transmitted from the periphery to the central nervous system by the axon of the primary afferent nociceptor.
This neuron has its cell body in the dorsal root ganglion and a long axon process that divides and sends a branch to the periphery and another to the spinal cord. The axons of the primary afferent nociceptors are relatively thin and conduct impulses slowly.
Pathways of pain in the central nervous system
Primary afferent nociceptors transmit impulses to the spinal cord (or if they arise from the head, the brainstem medulla).
In the spinal cord, primary afferent nociceptors terminate near second-order nerve cells in the dorsal horn of gray matter. Primary afferent nociceptors release chemical transmitters from their spinal terminals.
These transmitters activate second-order pain transmission cells. The identity of these transmitters has not been established. Still, candidates include small polypeptides such as substance P and somatostatin and amino acids such as glutamic or aspartic acid.
The axons of some of these second-order cells cross to the opposite side of the spinal cord and project long distances to the brainstem and thalamus. The route for pain transmission is in the anterolateral quadrant of the spinal cord.
Most of our information on the anatomy and physiology of pain transmission pathways in the central nervous system is derived from animal studies.
However, it is known that in humans, lesions of this anterolateral pathway permanently impair the sensation of pain and that electrical stimulation of the same causes pain.
There are two main targets for ascending nociceptive axons in the anterolateral quadrant of the spinal cord: the thalamus and the medial reticular formation of the brainstem.
Our knowledge is most extensive for spinal cells whose axons project directly into the thalamus, the spinothalamic tract cells.
The spinothalamic pathway is involved in the perception of human pain because injuries to it, at any level, produce lasting alterations in the sensation of pain.
The other main ascending nociceptive pathway in the anterolateral quadrant is the spinoreticular tract. The medullary reticular formation receives a large direct projection from the spinal cord and the branches of some spinal neurons that project into the thalamus.
Sensory versus affective aspects of pain
Noxious stimuli’ processes set in motion can be divided into two broad categories. On the one hand, the sensory processes lead to the detection and identification of the stimulus.
On the other hand, presumably due to the tissue-damaging potential of the noxious stimulus, aversive behavioral sequelae, such as withdrawal and escape, can terminate the trigger and protect the body. About these two categories of response, there are two subjective aspects of pain: sensory and affective.
The sensory aspects refer to the detection, location, evaluation of the intensity, and stimulus identification. Focusing on the sensory elements, a person may describe their pain as a mild burning pain located on the back of the hand.
In contrast, pain’s practical or unpleasant aspect correlates with the aversive drive to terminate the noxious stimulus. It is described by terms not explicitly linked to a sensory experience, e.g., persistent, uncomfortable, or unbearable.
The affective aspects would also be accompanied by changes in mood, such as anxiety and depression, which are generally considered psychological rather than sensory.
The difference between pain’s sensory and affective aspects can be further illustrated by the distinction between pain threshold and tolerance.
For example, if one delivers calibrated thermal stimuli to the skin, most people will report that the sensation becomes painful in a narrow range of skin temperatures (43-46ºC). The temperature called sad 50 percent of the time would be pain detection or sensory threshold.
The processes above were discussed in terms of a highly reliable pain transmission system, assuming that pain intensity is a direct function of nociceptive activity.
Indeed, the excellent correlation between stimulus intensity, impulses in primary afferent nociceptors, and reported pain intensity demonstrated in human subjects under experimental conditions often does not apply to the clinical situation.
The most notable observations are those in which patients subjected to injuries that should be very painful do not report significant pain.
A hypothesis for spontaneous analgesia arose when it was discovered that electrical stimulation of specific brain regions blocks responses to noxious stimulation in laboratory animals.
The failure of the pain suppression system has been suggested to represent certain types of chronic pain states, but most pain experts consider this conclusion premature. Much more work is needed to determine how this pain modulating network operates in chronic pain.
Physiological processes that improve pain and can lead to chronicity
One of the problems for patients, physicians, and disability examiners is how to explain pain experiences that seem disproportionate to objectively verifiable physical findings or illness or injury.
Although it is well known and accepted that various psychosocial factors could potentiate pain, the role of different physiological processes in the amplification and maintenance of pain may not be adequately considered when evaluating patient complaints.
Tissue damage initiates a variety of processes that sustain and amplify pain. With repeated stimuli, the thresholds of the primary afferent nociceptors progressively decrease so that ordinarily innocuous stimuli become painful.
For some primary afferent nociceptors, repeated noxious stimuli can induce continuous activity that lasts for several hours. The most familiar example of this is sunburn, in which the skin becomes a source of pain.
Hot water applied to the skin is perceived as painful, and a friendly pat on the back is excruciating. Other examples are the sensitivity of a sprained ankle or an arthritic joint.
It is painful to bear weight or even move the affected joint in these situations. Sensitization is an essential feature of many and perhaps the most clinically significant pain, but its cellular mechanism is unknown.
Sympathetic Nervous System Hyperactivity
Patients with relatively minor injuries occasionally develop pain disproportionate to their damages. Such pain often becomes progressively worse rather than following the usual course of decline over time.
Notably, the pain persists well beyond when the original tissue-damaging process has ended. In addition, the location of the pain can be quite different from the site of the precipitating pathology.
In some of these patients, sympathetic nervous system overactivity plays a vital role in pain maintenance because selective blockage of the sympathetic outlet produces immediate and dramatic relief.
The pain is usually accompanied by signs of sympathetic hyperactivity, such as a cold sweaty limb (vasoconstrictor). In addition, the skin may be hypersensitive to the touch, as if the nociceptors were sensitized.
Over time, osteoporosis, arthritis, and muscle atrophy can develop, and permanent functional impairment can occur. This condition, called reflex sympathetic dystrophy, usually responds to sympathetic blocks and physical therapy.
Physiological studies in animals indicate that sympathetic outflow can induce the discharge of primary afferent nociceptors. This is most prominent in damaged and regenerative afferents and occurs in sensitized undamaged afferents.
Reflex sympathetic dystrophy syndrome is relatively rare in its complete form. Still, sympathetic activity could be a common factor in maintaining or amplifying pain that would typically fade as injured tissues heal.
If this were at ease, local signs of increased sympathetic activity could help provide objective evidence that a pain-producing disease process is present.
Nociceptor activity produces a sustained contraction in the muscles. This muscle contraction produces flexion in the extremities, a primitive form of retraction, presumably a protective movement.
Disease in the abdominal viscera (e.g., intestine, liver) causes tension in the abdominal wall muscles. Pain from musculoskeletal structures also causes contraction and tenderness in other muscles innervated by the same spinal segment.
There is evidence that this disseminated muscle contraction plays a vital role in clinically significant pain. In patients with persistent discomfort, it is common to find small areas in the pretty tender muscles.
Pressure on these myofascial trigger points can reproduce the patient’s pain, and locally anesthetizing the facts (or other manipulations of the issues) can relieve days or months.
The physiological basis for these trigger points is unknown, but clinical evidence suggests they are often involved in pain maintenance without ongoing tissue damage.
Self-Sufficient Pain Processes: Livingston’s “Vicious Circle”
From the material just discussed, clinical observations indicate that various processes are set in motion by stimuli that damage tissues and activate nociceptors.
In peripheral tissues, pain-producing substances are released that sensitize nociceptors so that ordinarily innocuous stimuli can activate them.
In addition, the nociceptors themselves release factors such as substance P, which in turn cause vasodilation, edema, and the release of sensitizing substances from non-neural cells.
These processes play a role in activating the host’s defenses against infection or toxins. However, they do prolong and amplify pain.
Damage to the peripheral or central nervous systems can lead to chronic pain. For example, pain is widespread in some diseases that affect the peripheral nerves, such as diabetes mellitus or alcohol toxicity.
Traumatic peripheral nerve injury is rarely painful, but it can be dramatic. Causalgia (heat pain) is an example of pain induced by a traumatic injury to a peripheral nerve.
Causalgia is a syndrome characterized by severe pain and signs of sympathetic nervous system hyperactivity. Similarly, central nervous system injuries are rarely painful, but the pain is severe and resistant to treatment when they are.
There are specific characteristics of neuropathic pain. It often begins several days or weeks after the injury that causes it and tends to get worse before stabilizing.
Sensory abnormalities usually accompany it, including, paradoxically, deficits in pain sensation and painful hyperresponsiveness to ordinarily innocuous stimuli.
The mechanisms of neuropathic pain are not fully understood, but several factors could contribute to them (Ochoa, 1982).
Damaged primary afferents, which presumably include nociceptors, acquire specific properties when they begin to regenerate. These include spontaneous, mechanical, and sympathetic nervous system activity sensitivity.
Acute pain versus chronic pain
Is there a physiological basis for differentiating between acute and chronic pain? Little is known about the effects of prolonged pain on the central nervous system.
There is some evidence that the transition from acute pain to chronic pain alters the neurophysiology of patients in a way that makes them somewhat different from those with acute pain.
In arthritic rats, for example, there are changes in the peripheral nerves that alter their range of response to applied stimuli, and there may also be changes in the central pathways for pain transmission.
Experiments with rats in which nerves have been damaged and observed over time have shown changes in the central nervous system, but it is unknown how these changes are related to pain.
People with recurring headaches, arthritis, low back pain, angina, or low-grade malignancies may have had pain for years. Complaints, treatment, and patient reactions may differ for each condition.
In some cases, psychological factors are important. These factors are critical in patients with low back pain, facial pain, and headaches and appear to be more prominent the more extended the pain persists.
Psychological and somatic factors are not entirely separated to maintain pain. For example, stress and anxiety increase muscle contraction and sympathetic output and are expected to exacerbate any ongoing pain problems they contribute.
Conversely, any treatment that induces relaxation will reduce these factors and decrease pain. This may be an essential connection between psychosocial and somatic factors that influence pain tolerance.
Possible Physiological Monitoring Methods
This chapter has briefly reviewed the anatomy, physiology, and pharmacology of nociceptive transduction, transmission, and modulation. These are objective and potentially observable phenomena initiated by stimuli that damage or threaten tissue.
As we learn more about the transduction process, measuring the concentration of substances in regions of ongoing tissue damage that activate or sensitize primary afferent nociceptors may be feasible.
This could estimate the level of stimulation of chemically sensitive nociceptors. The most promising technique is directly recording electrical activity in primary afferents. This is technically possible and used in research but is not currently available for general clinical use.
Monitoring the central pathways of pain transmission is not practical with available technology. Although theoretically possible, registering individual units within the human nervous system requires a potentially dangerous surgical procedure.
Evoked potential or multiple unit studies do not have the required specificity or spatial resolution to allow the collection of meaningful data on clinical pain. Technically it is possible to measure the chemicals released at spinal synapses by primary afferent nociceptors.
Suppose the concentration of such chemicals in cerebrospinal fluid could be correlated with the activity of primary afferent nociceptors or with the severity of clinical pain. In that case, this could provide evidence similar to that derived from recording the activity of primary afferents.
However, at this time, the transmitter (s) for the primary afferent nociceptors are unknown.
Another approach uses positron emission tomography (PET) to monitor metabolic activity in central nervous system pain pathways.
Positron emission tomography is a non-invasive scanning technique that can provide evidence of focal brain activity and the concentration of certain chemicals.
This technique requires that enough neurons are active in a large enough region for a long enough period to be detected. Due to the topographic organization of the cortex, this technique could be used to control the somatosensory cortex.
An accurate map of the body’s surface extends many millimeters from the crust. The representation of the face and the hand in this map is extensive, so it is possible to detect these regions’ continuous activity produced by the nociceptive entry.
There is no evidence that such measures show anything in chronic pain patients.
Indirect measurements, such as sympathetic nervous system activity (skin temperature or skin resistance) or muscle contraction in painful areas, may help provide objective evidence of sustained nociceptive delivery.
The measurement of skin temperature over large areas of the body’s surface, thermography, is being used clinically but is not yet widely accepted as a reliable indicator of pain.
Although they are simple, painless, and safe indicators of sympathetic function, indirect measures of pain delivery such as thermography can be misleading.
Sympathetic changes can be produced by nonspecific factors like surprise or anxiety that do not involve pain.
On the other hand, if changes in sympathetic activity are highly localized, persistent, and consistent with the reported location of the patient’s pain, routine assessment of sympathetic function with techniques such as thermography in patients with chronic pain could provide clues to the mechanisms. that hold the pain.