The province of medicine is to preserve and restore health and to relieve suffering. Understanding pain is essential to both of these goals. Because pain is universally understood as a signal of disease, it is the most common symptom that brings a patient to a physician’s attention. The function of the pain sensory system is to protect the body and maintain homeostasis. It does this by detecting, localizing, and identifying potential or actual tissue-damaging processes. Because different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of a patient’s pain lend important diagnostic clues. It is the physician’s responsibility to provide rapid and effective pain relief.

Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion. When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often present.

PERIPHERAL MECHANISMS

The primary afferent nociceptor

A peripheral nerve consists of the axons of three different types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons (Fig. 8-1). The cell bodies of primary sensory afferents are located in the dorsal root ganglia within the vertebral foramina. The primary afferent axon has two branches: one projects centrally into the spinal cord and the other projects peripherally to innervate tissues. Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest diameter afferent fibers, A-beta (Aβ), respond maximally to light touch and/or moving stimuli; they are present primarily in nerves that innervate the skin. In normal individuals, the activity of these fibers does not produce pain. There are two other classes of primary afferent nerve fibers: the small diameter myelinated A-delta (Aδ) and the unmyelinated (C) axons (Fig. 8-1). These fibers are present in nerves to the skin and to deep somatic and visceral structures. Some tissues, such as the cornea, are innervated only by Aδ and C fiber afferents. Most Aδ and C fiber afferents respond maximally only to intense (painful) stimuli and produce the subjective experience of pain when they are electrically stimulated; this defines them as primary afferent nociceptors (pain receptors). The ability to detect painful stimuli is completely abolished when conduction in Aδ and C fiber axons is blocked.

Individual primary afferent nociceptors can respond to several different types of noxious stimuli. For example, most nociceptors respond to heat; intense cold; intense mechanical distortion, such as a pinch; changes in pH, particularly an acidic environment; and application of chemical irritants including adenosine triphosphate (ATP), serotonin, bradykinin, and histamine.

Sensitization

When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors is lowered, and the frequency of firing is higher for all stimulus intensities. Inflammatory mediators such as bradykinin, nerve-growth factor, some prostaglandins, and leukotrienes contribute to this process, which is called sensitization. Sensitization occurs at the level of the peripheral nerve terminal (peripheral sensitization) as well as at the level of the dorsal horn of the spinal cord (central sensitization). Peripheral sensitization occurs in damaged or inflamed tissues, when inflammatory mediators activate intracellular signal transduction in nociceptors, prompting an increase in the production, transport, and membrane insertion of chemically gated and voltage-gated ion channels. These changes increase the excitability of nociceptor terminals and lower their threshold for activation by mechanical, thermal, and chemical stimuli. Central sensitization occurs when activity, generated by nociceptors during inflammation, enhances the excitability of nerve cells in the dorsal horn of the spinal cord. Following injury and resultant sensitization, normally innocuous stimuli can produce pain (termed allodynia). Sensitization is a clinically important process that contributes to tenderness, soreness, and hyperalgesia (increased pain intensity in response to the same noxious stimulus; e.g., moderate pressure causes severe pain). A striking example of sensitization is sunburned skin, in which severe pain can be produced by a gentle slap on the back or a warm shower.

Sensitization is of particular importance for pain and tenderness in deep tissues. Viscera are normally relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera do generate significant discomfort when distended. In contrast, when affected by a disease process with an inflammatory component, deep structures such as joints or hollow viscera characteristically become exquisitely sensitive to mechanical stimulation.

A large proportion of Aδ and C fiber afferents innervating viscera are completely insensitive in normal noninjured, noninflamed tissue. That is, they cannot be activated by known mechanical or thermal stimuli and are not spontaneously active. However, in the presence of inflammatory mediators, these afferents become sensitive to mechanical stimuli. Such afferents have been termed silent nociceptors, and their characteristic properties may explain how, under pathologic conditions, the relatively insensitive deep structures can become the source of severe and debilitating pain and tenderness. Low pH, prostaglandins, leukotrienes, and other inflammatory mediators such as bradykinin play a significant role in sensitization.

Nociceptor-induced inflammation

Primary afferent nociceptors also have a neuroeffector function. Most nociceptors contain polypeptide mediators that are released from their peripheral terminals when they are activated (Fig. 8-2). An example is substance P, an 11-amino-acid peptide. Substance P is released from primary afferent nociceptors and has multiple biologic activities. It is a potent vasodilator, degranulates mast cells, is a chemoattractant for leukocytes, and increases the production and release of inflammatory mediators. Interestingly, depletion of substance P from joints reduces the severity of experimental arthritis. Primary afferent nociceptors are not simply passive messengers of threats to tissue injury but also play an active role in tissue protection through these neuroeffector functions.

CENTRAL MECHANISMS

The spinal cord and referred pain

The axons of primary afferent nociceptors enter the spinal cord via the dorsal root. They terminate in the dorsal horn of the spinal gray matter (Fig. 8-3). The terminals of primary afferent axons contact spinal neurons that transmit the pain signal to brain sites involved in pain perception. When primary afferents are activated by noxious stimuli, they release neurotransmitters from their terminals that excite the spinal cord neurons. The major neurotransmitter released is glutamate, which rapidly excites dorsal horn neurons. Primary afferent nociceptor terminals also release peptides, including substance P and calcitonin gene-related peptide, which produce a slower and longer-lasting excitation of the dorsal horn neurons. The axon of each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents.

The convergence of sensory inputs to a single spinal pain-transmission neuron is of great importance because it underlies the phenomenon of referred pain. All spinal neurons that receive input from the viscera and deep musculoskeletal structures also receive input from the skin. The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies the afferent innervation of a structure. For example, the afferents that supply the central diaphragm are derived from the third and fourth cervical dorsal root ganglia. Primary afferents with cell bodies in these same ganglia supply the skin of the shoulder and lower neck. Thus, sensory inputs from both the shoulder skin and the central diaphragm converge on pain-transmission neurons in the third and fourth cervical spinal segments. Because of this convergence and the fact that the spinal neurons are most often activated by inputs from the skin, activity evoked in spinal neurons by input from deep structures is mislocalized by the patient to a place that roughly corresponds with the region of skin innervated by the same spinal segment. Thus, inflammation near the central diaphragm is often reported as shoulder discomfort. This spatial displacement of pain sensation from the site of the injury that produces it is known as referred pain.

Ascending pathways for pain

A majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons form the contralateral spinothalamic tract, which lies in the anterolateral white matter of the spinal cord, the lateral edge of the medulla, and the lateral pons and midbrain. The spinothalamic pathway is crucial for pain sensation in humans. Interruption of this pathway produces permanent deficits in pain and temperature discrimination.

Spinothalamic tract axons ascend to several regions of the thalamus. There is tremendous divergence of the pain signal from these thalamic sites to several distinct areas of the cerebral cortex that subserve different aspects of the pain experience (Fig. 8-4). One of the thalamic projections is to the somatosensory cortex. This projection mediates the purely sensory aspects of pain, i.e., its location, intensity, and quality. Other thalamic neurons project to cortical regions that are linked to emotional responses, such as the cingulate gyrus and other areas of the frontal lobes, including the insular cortex. These pathways to the frontal cortex subserve the affective or unpleasant emotional dimension of pain. This affective dimension of pain produces suffering and exerts potent control of behavior. Because of this dimension, fear is a constant companion of pain. As a consequence, injury or surgical lesions to areas of the frontal cortex activated by painful stimuli can diminish the emotional impact of pain while largely preserving the individual’s ability to recognize noxious stimuli as painful.

PAIN MODULATION

The pain produced by injuries of similar magnitude is remarkably variable in different situations and in different individuals. For example, athletes have been known to sustain serious fractures with only minor pain, and Beecher’s classic World War II survey revealed that many soldiers in battle were unbothered by injuries that would have produced agonizing pain in civilian patients. Furthermore, even the suggestion that a treatment will relieve pain can have a significant analgesic effect (the placebo effect). On the other hand, many patients find even minor injuries (such as venipuncture) frightening and unbearable, and the expectation of pain can induce pain even without a noxious stimulus. The suggestion that pain will worsen following administration of an inert substance can increase its perceived intensity (the nocebo effect).

The powerful effect of expectation and other psychological variables on the perceived intensity of pain is explained by brain circuits that modulate the activity of the pain-transmission pathways. One of these circuits has links to the hypothalamus, midbrain, and medulla, and it selectively controls spinal pain-transmission neurons through a descending pathway (Fig. 8-4).

Human brain–imaging studies have implicated this pain-modulating circuit in the pain-relieving effect of attention, suggestion, and opioid analgesic medications (Fig. 8-5). Furthermore, each of the component structures of the pathway contains opioid receptors and is sensitive to the direct application of opioid drugs. In animals, lesions of this descending modulatory system reduce the analgesic effect of systemically administered opioids such as morphine. Along with the opioid receptor, the component nuclei of this pain-modulating circuit contain endogenous opioid peptides such as the enkephalins and β-endorphin.