pain

pain, complex experience consisting of a physiological and a psychological response to a noxious stimulus. Pain is a warning mechanism that protects an organism by influencing it to withdraw from harmful stimuli; it is primarily associated with injury or the threat of injury.

Pain is subjective and difficult to quantify, because it has both an affective and a sensory component. Although the neuroanatomic basis of pain reception develops before birth, individual pain responses are learned in early childhood and are affected by social, cultural, psychological, cognitive, and genetic factors, among others. Those factors account for differences in pain tolerance among humans. Athletes, for example, may be able to withstand or ignore pain while engaged in a sport, and certain religious practices may require participants to endure pain that seems intolerable to most people.

An important function of pain is to alert the body to potential damage. That is accomplished through nociception, the neural processing of harmful stimuli. The pain sensation, however, is only one part of the nociceptive response, which may include an increase in blood pressure, an increase in heart rate, and a reflexive withdrawal from the noxious stimulus. Acute pain can arise from breaking a bone or touching a hot surface. During acute pain, an immediate intense feeling of short duration, sometimes described as a sharp pricking sensation, is followed by a dull throbbing sensation. Chronic pain, which is often associated with diseases such as cancer or arthritis, is more difficult to locate and treat. If pain cannot be alleviated, psychological factors such as depression and anxiety can intensify the condition.

Early conceptions of pain

Pain is a physiological and psychological element of human existence, and thus it has been known to humankind since the earliest eras, but the ways in which people respond to and conceive of pain vary dramatically. In certain ancient cultures, for example, pain was deliberately inflicted on individuals as a means of pacifying angry gods. Pain was also seen as a form of punishment, inflicted on humans by gods or demons. In ancient China, pain was thought to arise from an imbalance between the two complementary forces of life, yin and yang. Ancient Greek physician Hippocrates believed that pain is associated with too much or too little of one of the four humours (blood, phlegm, yellow bile, or black bile). Muslim physician Avicenna believed that pain is a sensation that originated with a change in the physical condition of the body.

Theories of pain

Medical understanding of the physiological basis of pain is a comparatively recent development, having emerged in earnest in the 19th century. At that time, various British, German, and French physicians recognized the problem of chronic “pains without lesion” and attributed them to a functional disorder or persistent irritation of the nervous system. German physiologist and comparative anatomist Johannes Peter Müller’s concept of Gemeingefühl, or “cenesthesis,” an individual’s ability to correctly perceive internal sensations, was another of the creative etiologies proposed for pain. American physician and author S. Weir Mitchell observed Civil War soldiers afflicted with causalgia (constant burning pain; later known as complex regional pain syndrome), phantom limb pain, and other painful conditions long after their original wounds had healed. Despite the odd and often hostile behaviour of his patients, Mitchell was convinced of the reality of their physical suffering.

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By the late 1800s the development of specific diagnostic tests and the identification of specific signs of pain were beginning to redefine the practice of neurology, leaving little room for chronic pains that could not be explained in the absence of other physiological symptoms. At the same time, practitioners of psychiatry and the emerging field of psychoanalysis found that “hysterical” pains offered potential insights into mental and emotional disease. The contributions of individuals such as English physiologist Sir Charles Scott Sherrington supported the concept of specificity, according to which “real” pain was a direct one-to-one response to a specific noxious stimulus. Sherrington introduced the term nociception to describe the pain response to such stimuli. Specificity theory suggested that individuals who reported pain in the absence of an evident cause were delusional, neurotically obsessed, or malingering (often the conclusion of military surgeons or those treating workmen’s compensation cases). Another theory, which was popular with psychologists at the time but was soon after abandoned, was intensive pain theory, in which pain was considered to be an emotional state, incited by unusually intense stimuli.

In the 1890s German neurologist Alfred Goldscheider endorsed Sherrington’s insistence that the central nervous system integrates inputs from the periphery. Goldscheider proposed that pain is a result of the brain’s recognition of spatial and temporal patterns of sensation. French surgeon René Leriche, who worked with injured soldiers during World War I, suggested that a nerve injury that damages the myelin sheath surrounding the sympathetic nerves (the nerves involved in the fight-or-flight response) might lead to sensations of pain in response to normal stimuli and internal physiological activity. American neurologist William K. Livingston, who worked with patients with industrial injuries in the 1930s, diagrammed a feedback loop within the nervous system, which he described as a “vicious circle.” Livingston theorized that severe lasting pain induces functional and organic changes in the nervous system, thereby producing a chronic pain state.

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The various theories on pain, however, were largely ignored until World War II, when organized teams of clinicians began to observe and treat large numbers of individuals with similar injuries. In the 1950s American anesthesiologist Henry K. Beecher, using his experiences of treating civilian patients and wartime casualties, found that soldiers with serious wounds frequently seemed to be in much less pain than civilian surgical patients. Beecher concluded that pain is the result of a fusion of physical sensation with a cognitive and emotional “reaction component.” Thus, the mental context of pain is important. Pain for the surgical patient meant a disruption of normal life and fears of serious illness, whereas pain for the wounded soldier meant release from the battlefield and an increased chance of survival. Therefore, the assumptions of specificity theory, which were based on laboratory experiments in which the reaction component was relatively neutral, could not be applied to the understanding of clinical pain. Beecher’s conclusions were supported by the work of American anesthesiologist John Bonica, who in his book The Management of Pain (1953) considered clinical pain to include both physiological and psychological components.

Dutch neurosurgeon Willem Noordenbos extended the theory of pain as an integration of multiple inputs into the nervous system in his short but classic book, Pain (1959). Noordenbos’s ideas appealed to Canadian psychologist Ronald Melzack and British neuroscientist Patrick David Wall. Melzack and Wall combined the ideas of Goldscheider, Livingston, and Noordenbos with available research evidence and in 1965 proposed the so-called gate control theory of pain. According to gate control theory, the perception of pain depends on a neural mechanism in the substantia gelatinosa layer of the dorsal horn of the spinal cord. The mechanism acts as a synaptic gate that modulates the pain sensation from myelinated and unmyelinated peripheral nerve fibres and the activity of inhibitory neurons. Thus, stimulation of nearby nerve endings can inhibit the nerve fibres that transmit pain signals, which explains the relief that can occur when an injured area is stimulated by pressure or rubbing. Although the theory itself proved to be incorrect, the implication that laboratory and clinical observations together could demonstrate the physiological basis of a complex neural integration mechanism for pain perception inspired and challenged a young generation of researchers.

In 1973, drawing on the upsurge of interest in pain generated by Wall and Melzack, Bonica organized a meeting among interdisciplinary pain researchers and clinicians. Under Bonica’s leadership, the conference, which was held in the United States, gave birth to an interdisciplinary organization known as the International Association for the Study of Pain (IASP) and a new journal titled Pain, initially edited by Wall. The formation of IASP and the launch of the journal marked the emergence of pain science as a professional field.

In the following decades, research on the problem of pain expanded significantly. From that work, two major findings emerged. First, severe pain from an injury or other stimulus, if continued over some period, was found to alter the neurochemistry of the central nervous system, thereby sensitizing it and giving rise to neuronal changes that endure after the initial stimulus is removed. That process is perceived as chronic pain by the affected individual. The involvement of neuronal changes in the central nervous system in the development of chronic pain was demonstrated across multiple studies. In 1989, for example, American anesthesiologist Gary J. Bennett and Chinese scientist Xie Yikuan demonstrated the neural mechanism underlying the phenomenon in rats with constrictive ligatures placed loosely around the sciatic nerve. In 2002 Chinese-born neuroscientist Min Zhuo and colleagues reported the identification of two enzymes, adenylyl cyclase types 1 and 8, in the forebrains of mice that play an important role in sensitizing the central nervous system to pain stimuli.

The second finding that emerged was that pain perception and response differ with gender and ethnicity and with learning and experience. Women appear to suffer pain more often and with greater emotional stress than do men, but some evidence shows that women may cope with severe pain more effectively than men. African Americans show a higher vulnerability to chronic pain and a higher level of disability than do white patients. Those observations have been borne out by neurochemical research. For example, in 1996 a team of researchers led by American neuroscientist Jon D. Levine reported that different types of opioid drugs produce different levels of pain relief in women and men. Other research conducted in animals suggested that pain experiences early in life can produce neuronal changes at the molecular level that influence an individual’s pain response as an adult. A significant conclusion from those studies is that no two individuals experience pain the same way.