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. Thus, understanding pain is very essential in order to preserve and restore health and to relieve suffering. The function of the pain sensory system is to protect the body and maintain homeostasis. It does this by detecting, localizing, and identifying tissue- damaging processes. Since different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of a patient's pain complaint and the location of tenderness provide important diagnostic clues and are used to evaluate the response to treatment. Once this information is obtained, it is the obligation of the physician 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 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. The cell bodies of primary afferents are located in the dorsal root ganglia in the vertebral foramina. The primary afferent axon bifurcates to send one process into the spinal cord and the other to innervate tissues.
Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest-diameter 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 afferents: the small-diameter myelinated
A-delta (Aδ) and the unmyelinated (C fiber) axons . 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 afferents. Most Aδ and C 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 Aδ and C axons are blocked. Individual primary afferent nociceptors can respond to several different types of noxious stimuli. For example, most nociceptors respond to heating, intense mechanical stimuli such as a pinch, and application of irritating chemicals.
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, some prostaglandins, and leukotrienes contribute to this process, which is called sensitization. In sensitized tissues normally innocuous stimuli can produce pain. Sensitization is a clinically important process that contributes to tenderness, soreness, and hyperalgesia. 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.
Fig 2. Events leading to activation, sensitization, and spread of sensitization of primary afferent nociceptor terminals. A. Direct activation by intense pressure and consequent cell damage. Cell damage induces lower pH (H⁺)and leads to release of potassium (K⁺)and to synthesis of prostaglandins (PG) and bradykinin (BK). Prostaglandins increase the sensitivity of the terminal to bradykinin and other pain-producing substances. B. Secondary activation. Impulses generated in the stimulated terminal propagate not only to the spinal cord but also into other terminal branches where they induce the release of peptides, including substance P (SP).Substance P causes vasodilation and neurogenic edema with further accumulation of bradykinin. Substance P also causes the release of histamine (H) from mast cells and serotonin (5HT) from platelets.
A large proportion of Aδ and C 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 One important concept to emerge in recent years is that afferent nociceptors also have a neuroeffector function. Most nociceptors contain polypeptide mediators that are released from their peripheral terminals when they are activated . 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 . The terminals of primary afferent axons contact spinal neurons that transmit the pain signal to brain sites involved in pain perception. 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 paintransmission 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 is roughly coextensive with the region of skin innervated by the same spinal segment.
Thus inflammation near the central diaphragm is usually reported as discomfort near the shoulder. This spatial displacement of pain sensation from the site of the injury that produces it is known as referred pain.
Fig 3. The convergence-projection hypothesis of referred pain. According to this hypothesis, visceral afferent nociceptors converge on the same pain-projection neurons as the afferents from the somatic structures in which the pain is perceived. The brain has no way of knowing the actual source of input and mistakenly "projects" the sensation to the somatic structure.
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 broad areas of the cerebral cortex that subserve different aspects of the pain experience. 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. 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.
PAIN MODULATION
The pain produced by similar injuries 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 of relief can have a significant analgesic effect (placebo).
Fig 4.
A. Transmission system for nociceptive messages. Noxious stimuli activate the sensitive peripheral ending of the primary afferent nociceptor by the process of transduction. The message is then transmitted over the peripheral nerve to the spinal cord, where it synapses with cells of origin of the major ascending pain pathway, the spinothalamic tract. The message is relayed in the thalamus to the anterior cingulate (C), frontal insular (F), and somatosensory cortex (SS).
B. Pain-modulation network. Inputs from frontal cortex and hypothalamus (Hyp.)activate cells in the midbrain that control spinal pain-transmission cells via cells in the medulla.
On the other hand, many patients find even minor injuries (such as venipuncture) frightening and unbearable, and the expectation of pain has been demonstrated to induce pain without a noxious stimulus. The powerful effect of expectation and other psychological variables on the perceived intensity of pain implies the existence of brain circuits that can modulate the activity of the pain-transmission pathways. One of these circuits has links in the hypothalamus, midbrain, and medulla, and it selectively controls spinal pain-transmission neurons through a descending pathway.
Human brain imaging studies have implicated this pain-modulating circuit in the pain-relieving effect of attention, suggestion, and opioid analgesic medications. 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 the 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 endorphin.
The most reliable way to activate this endogenous opioid-mediated modulating system is by prolonged pain and/or fear. There is evidence that pain-relieving endogenous opioids are released following surgical procedures and in patients given a placebo for pain relief.
Pain-modulating circuits can enhance as well as suppress pain. Both pain-inhibiting and pain-facilitating neurons in the medulla project to and control spinal pain-transmission neurons. Since pain-transmission neurons can be activated by modulatory neurons, it is theoretically possible to generate a pain signal with no peripheral noxious stimulus. In fact, functional imaging studies have demonstrated increased activity in this circuit during migraine headache. A central circuit that facilitates pain could account for the finding that pain can be induced by suggestion and could provide a framework for understanding how psychological factors can contribute to chronic pain.
NEUROPATHIC PAIN
Lesions of the peripheral or central nervous pathways for pain typically result in a loss or impairment of pain sensation.
Paradoxically, damage or dysfunction of these pathways can produce pain. For example, damage to peripheral nerves, as occurs in diabetic neuropathy, or to primary afferents, as in herpes zoster, can result in pain that is referred to the body region innervated by the damaged
nerves. Though rare, pain may also be produced by damage to the central nervous system, particularly the spinothalamic pathway or thalamus. Such neuropathic pains are often severe and are notoriously intractable to standard treatments for pain. Neuropathic pains typically have an unusual burning, tingling, or electric shock–like quality and may be triggered by very light touch.
These features are rare in other types of pain. On examination, a sensory deficit is characteristically present in the area of the patient's pain. Hyperpathia is also characteristic of neuropathic pain; patients often complain that the very lightest moving stimuli evoke exquisite pain (allodynia). In this regard it is of clinical interest that a topical preparation of 5% lidocaine in patch form is effective for patients with postherpetic neuralgia who have prominent allodynia.
A variety of mechanisms contribute to neuropathic pain. As with sensitized primary afferent nociceptors, damaged primary afferents, including nociceptors, become highly sensitive to mechanical stimulation and begin to generate impulses in the absence of stimulation. There is evidence that this increased sensitivity and spontaneous activity is due to an increased concentration of sodium channels.
Damaged primary afferents may also develop sensitivity to norepinephrine. Interestingly, spinal cord pain-transmission neurons cut off from their normal input may also become spontaneously active. Thus both central and peripheral nervous system hyperactivity contribute to neuropathic pain.
Sympathetically Maintained Pain Patients with peripheral nerve injury can develop a severe burning pain (causalgia) in the region innervated by the nerve. The pain typically begins after a delay of hours to days or even weeks. The pain is accompanied by swelling of the extremity, periarticular osteoporosis, and arthritic changes in the distal joints. The pain is dramatically and immediately relieved by blocking the sympathetic innervation of the affected extremity. Damaged primary afferent nociceptors acquire adrenergic sensitivity and can be activated by stimulation of the sympathetic outflow. A similar syndrome called reflex sympathetic dystrophy can be produced without obvious nerve damage by a variety of injuries, including fractures of bone, soft tissue trauma, myocardial infarction, and stroke .
Although the pathophysiology of this condition is poorly understood, the pain and the signs of inflammation are rapidly relieved by blocking the sympathetic nervous system. This implies that sympathetic activity can activate undamaged nociceptors when inflammation is present. Signs of sympathetic hyperactivity should be sought in patients with posttraumatic pain and inflammation and no other obvious explanation.
