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PART III INFLUENCES ON PAIN AND PAIN BEHAVIOR
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7 The Anatomy and Physiology of Pain pain is a subjective experience with two comple- mentary aspects: one is a localized sensation in a particular body part; the other is an unpleasant quality of varying severity commonly associated with behaviors directed at relieving or terminating the experience. Pain has much in common with other sensory modalities (National Academy of Sciences, 19851. First, there are specific pain receptors. These are nerve endings, present in most body tissues, that only respond to damaging or potentially damaging stimuli. Second, the messages initiated by these noxious stimuli are transmitted by spe- cific, identified nerves to the spinal cord. The sensitive nerve ending in the tissue and the nerve attached to it together form a unit called the primary afferent nociceptor. The primary afferent nociceptor contacts second-order pain-transmission neurons in the spinal cord. The second- order cells relay the message through well-defined pathways to higher centers, including the brain stem reticular formation, thalarnus, somato- sensory cortex, and limbic system. It is thought that the processes unclerlying pain perception involve primarily the thalamus and cortex. In this chapter we review the anatomy and physiology of pain pathways. We also discuss some of the physiological processes that modify the pain experience and that may contribute to the develop- ment of chronicity. For obvious reasons, most of this information comes from animal experiments. However, in recent years, experimental studies of human subjects using physiological, pharmacological, and psychophysical methods indicate that much of what has been learned 123
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124 INFLUENCES ONP~N~DPMN BEHAVIOR in animals is applicable to humans (National Academy of Sciences, 19851. Research into basic mechanisms underlying pain is an increas- ingly exciting and promising area. However, most of what is known about the anatomy and physiology of pain is from studies of experi- mentally induced cutaneous (skin) pain, while most clinical pain arises from deep tissues. Thus, while experimental studies provide fairly good models for acute pain, they are poor models for clinical syndromes of chronic pain. Not only do they provide little information about the muscles, joints, and tendons that are most often affected by chronically painful conditions, but they do not address the vast array of psycho- social factors that influence the pain experience profoundly. To im- prove our understanding and treatment of pain we will need better animal models of human pain and better tools for studying clinical pain. PAIN PROCESSES Figure 7-1 illustrates the major components of the brain systems involved in processing pain-related information. There are four major 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 by which the message is carried 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 transmis- sion system. Perception is the subjective awareness produced by sensory signals; it involves the integration of many sensory messages into ~ coherent and meaningful whole. Perception is a complex function of several processes, including attention, expectation, and interpretation. Transduction, transmission, and modulation are neural processes that can be studied objectively using methods that involve direct observation. In contrast, although there is unquestionably a neural basis for it, the awareness of pain is a perception and, therefore, subjective, so it cannot be directly and objectively measured. Even if we could measure the activity of pain-transmission neurons in another person, concluding that that person feels pain would require an inference based on indirect evidence. Transduction Three types of stimuli can activate pain receptors in peripheral tissues: mechanical (pressure, pinch), heat, and chemical. Mechanical
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ANATOMY AND PHYSIOLOGY OF PEN 125 TRANSMISSION SYSTEM Frontal (association) cortex Somatosenso Diencephalon ~ \A~ <4 cortex Mldbraln v\\? r Direct Reticulothalamic Pathway Medulla ANY Tissue DRG \ Transduction Spinothalamic Pathwav ~> ~~ Anterolateral Pathway MODULATION SYSTEM I ~ H ' 4W t _: /~ Tissue DRG / | Brain stem I FIGURE 7-1 Diagrammatic outline of the major neural structures relevant to pain. The sequence of events leading to pain perception begins in the transmission system with transduction (lower left), in which a noxious stimulus produces nerve impulses in the primary adherent nociceptor. These impulses are conducted to the spinal cord, where the primary afferent nociceptors contact the central pain- transmission cells. The central pain-transmission cells relay the message to the thalamus either directly via the spinothalamic tract or indirectly via the reticular formation and the reticulothalamic pathway. From the thalamus, the message is relayed to the cerebral cortex. (DRG: dorsal root ganglion.) The pain-modulation system has inputs Mom the frontal association cortex and the hypothalamus (H). The outflow is through the midbrain and medulla to the dorsal horn of the spinal cord, where it inhibits pain-transm~ssion cells, thereby reducing the intensity of . . . perceived pam. and heat stimuli are usually brief, whereas chemical stimuli are usually long lasting. Nothing is known about how these stimuli activate nociceptors. The nociceptive nerve endings are so small and scattered that they are difficult to find, let alone study. Nonetheless, there have been some studies of the effects of chemicals on the firing frequency of identified primary afferent nociceptors.
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126 INFLUENCES ONP~N~DP~N BEHAVIOR A variety of pain-producing chemicals activate or sensitize primary afferent nociceptors (Bisgaard and Kristensen, 1985; Juan and Lembeck, 1974; Keele, 19661. Some of them, such as potassium, histamine, and serotonin, may be released by damaged tissue cells or by the circulating blood cells that migrate out of blood vessels into the area of tissue damage. Other chemicals, such as bradykinin, prosta- glandins, and leukotrienes, are synthesized by enzymes activated by tissue damage (Armstrong, 1970; Ferreira, 1972; Moncada et al., 1985; Vane, 19711. All of these pain-producing chemicals are found in increased concentrations in regions of inflammation as well as pain. Obviously, the process of transduction involves a host of chemical processes that probably act together to activate the primary afferent nociceptor. In theory, any of these substances could be measured to give an estimate of the peripheral stimulus for pain. In practice, such assays are not available to clinicians. It should be pointed out that most of our knowledge of primary afferent nociceptors is derived from studies of cutaneous nerves. Although this work is of general importance, the bulk of clinically significant pain is generated by processes in deep musculoskeletal or visceral tissues. Scientists are beginning to study the stimuli that activate nociceptors in these deep tissues (Cervero, 1982, 1985; Coggeshall et al., 1983; National Academy of Sciences, 1985~. In muscle, there are primary adherent nociceptors that respond to pres- sure, muscle contraction, and irritating chemicals (Kumazawa and Mizumura, 1977; Mense and Meyer, 1985; Mense and Stahnke, 19831. Muscle contraction under conditions of ischemia is an especially potent stimulus for some of these nociceptors. Despite progress in our understanding of the physiology of muscu- loskeletal nociceptors, we still know very little about the mechanisms underlying common clinical problems such as low back pain. Even when there is degeneration of the spine and compression of a nerve rooWa condition generally acknowledged to be extremely painful we do not know which nociceptors are activated or how they are activated. Neither do we know what it is about the process that leads to pain. Transmission 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 process, the axon, that divides and sends one branch out to the
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ANATOMY AND PHYSIOLOGY OF PAIN 127 /: Peripheral Receptive Fleld - - PerTpheral Process Cell Body Dorsal Horn me, To Brain Central Process ( If Spinal Cord FIGURE 7-2 The primal adherent nociceptor. This is the route by which the central nervous system is informed of impending or actual tissue damage. Its peripheral process runs in peripheral nerves, and its peripheral terminals are present In most body structures These terminals are sensitive to noxious heat, mechanical stimulation, end or pain-producing chemicals. The central process enters the spinal cord via the dorsal root and terminates on central pain- transmission cells that relay the info~-l~ation to higher centers. Both peripheral and central processes are maintained by the cell body in the dorsal root ganglion, which is near, but not in, the spinal cord. periphery and one into the spinal cord (Figure 7-21. The axons of primary afferent nociceptors are relatively thin and conduct impulses slowly. It is possible to place an electrode into a human peripheral nerve and record the activity of primary afferent nociceptors (Fitzgerald and Lynn, 1977; Torebdork and Hallin, 19731. The nociceptor is character- ized by its response to noxious heat, pressure, or chemical stimuli. The "pain" message is coded in the pattern and frequency of impulses in the axons of the primary afferent nociceptors. There is a direct relation between the intensity of the stimulus and the frequency of nociceptor discharge (Figure 7-31. Furthermore, combined neurophysiological and psychophysical studies in humans have shown a direct relation be- tween discharge frequency in a primary afferent nociceptor and the reported intensity of pain (Fitzgerald and Lynn, 1977; LaMotte et al., 19831. Blocking transmission in the small-diameter axons of the nociceptors blocks pain, whereas blocking activity of the larger- diameter axons in a peripheral nerve does not. These identified primary afferent nociceptors are thus necessary for detecting noxious stimuli. Monitoring activity in identified primary afferent nociceptors is a potential too] for the evaluation of certain types of clinical pain. In fact, this method has been used clinically to demonstrate pain-producing neural activity arising from a damaged nerve (Nystrom and Hagbarth, 19811. At present, this method should be considered just a research tool; however, it is technically feasible and is of great potential value
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128 INFLUENCES ON PAIN AND PAIN BEHAVIOR 7 ~ 5 a) Be Be ,j, 3 C' m In Strong pain / / Faint pain / ~ 20: FEW rmth' ~ 6~ 1 _ _ C' ~ 1 1 40 45 50 1_ I ~ , I , ~ , , I TEMPERATURE (°C) 40 45 50 TEMPERATURE (°C) c,, 20 15 an to o Pai: _4 1 2 3 4 5 6 SUBJECTIVE INTENSITY FIGURE 7-3 The relation of discharge frequency in primary aiferent nociceptors to subjective pain intensity in human subjects. Top left: The skin of human subjects was subjected to brief, calibrated temperature increases. Subjects began to identify the temperature as painful at about 45°C; with increasing temperature, the reported pain intensity also increased. Top right: Using the same range of tempera- tures, discharge in primate primary aiferent nociceptors (with unmyelinated axons) was recorded. These afferents were not active prior to stimulation and only began to fire at temperatures near the h',rnan pain threshold. The increase in their firing is quite similar to the increase in subjective pain ratings of Herman subjects across the same temperature range (Lamotte and Campbell, 1978). (C-PMN: C-polymodal nociceptor.) Bottom: Identified unmyelinated adherents were recorded in awake human subjects. In these subjects, calibrated thermal stimuli were delivered to the skin region innervated by the nerves that were recorded. Nociceptor discharge and subjective pain intensity were measured concurrently. There is a direct, though nonlinear relation between them (Gybels et al., 1979).
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ANATOMY AND PHYSIOLOGY OF PIN 129 for evaluating pain patients. It raises the possibility of actually demonstrating nociceptor activity coming from a painful area. This method could be an advance over other correlative techniques for assessing pain because it measures the presumed noxious input, that is, the neural activity that ordinarily causes pain. Most of the other measures assess responses that could be, but are not necessarily, caused by noxious stimuli. It is important to point out that (1) there can be pain without activity in primary afEerent nociceptors, and (2) there can be activity in primary afferent nociceptors without pain. These phenomena occur when there has been damage to the central or peripheral nervous systems. In addition, the modulating system can suppress central transmission of activity elicited by nociceptor input. Thus, there is a variable relation between nociceptor input and perceived pain inten- sity. For this reason the method of recording primary afferent nociceptors could be used to confirm the presence of an input, but it could not be used to prove that pain was not present. Besides these theoretical limitations of trying to assess subjective pain intensity by recording primary afferent nociceptors, there are important practical problems in measuring either pain-producing substances or primary afferent nociceptor activity. One is that the largest group of patients disabled by pain localize it to muscuToskeletal structures in the lower back. Because the nerves innervating these structures are not near the skin, they are difficult to find. Another problem is that pain arising from deep structures is often felt at sites distant from where the tissue damage occurs. In contrast to the pain produced by skin damage, which is sharp or burning and well localized to the site of injury, the pain that arises from deep tissue injury is generally aching, dull, and poorly localized (Lewis, 19421. When the damage to deep tissues is severe or long lasting, the sensation it produces may be misperceived as arising from a site that is distant from the actual site of damage (Head, 1893; Keligren, 1938; Lewis, 1942; Sinclair et al., 19481. This phenomenon, known as referre~pain, helps to explain the frequent discrepancy between physical findings and patient complaints. The mechanism of referred pain is unknown for any particular case. Referred pain can be a major source of confusion in the examination of patients complaining primarily of pain. The fact that pain is referred from visceral internal organs to somatic body structures is well known and commonly used by physicians. For example, the pain of a heart attack is not always localized to the heart but commonly is felt diffusely in the chest, the left arm, and sometimes in the upper
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130 INFLUENCES ON PEN ED PEN BEHAVIOR abdomen. Less widely recognized is the fact that irritable spots, such as myofascial trigger points, in skeletal muscles also cause feelings of pain in locations distant from the irritable spot. This was demon- strated experimentally in muscle and fascia by KelIgren in the late 1930s (Keligren, 19381. Specific patterns of pain referred from partic- ular muscles have been described clinically (Travel! and Rir~zler, 1952; Travell and Simons, 19831. (See Chapter 10 end appendix.) At least four physiological mechanisms have been proposed to explain referred pain: (1) activity in sympathetic nerves, (2) peripheral branching of primary afferent nociceptors, (3) convergence projection, and (4) convergence facilitation. The latter two involve primarily central nervous system mechanisms. 1. Sympathetic nerves may cause referred pain by releasing sub- stances that sensitize primary afferent nerve endings in the region of referred pain (Procacci and Zoppi, 1981), or possibly by restricting the flow of blood in the vessels that nourish the sensory nerve fiber itself. 2. Peripheral branching of a nerve to separate parts of the body causes the brain to misinterpret messages originating from nerve endings in one part of the body as coming from the nerve branch supplying the other part of the body. 3. According to the convergence-projection hypothesis, a single nerve cell in the spinal cord receives nociceptive input both from the internal organs and from nociceptors coming from the skin and muscles. The brain has no way of distinguishing whether the excita- tion arose from the somatic structures or from the visceral organs. It is proposed that the brain interprets any such messages as coming from skin and muscle nerves rather than from an internal organ. The convergence of visceral and somatic sensory inputs onto pain projec- tion neurons in the spinal cord has been demonstrated (Milne et al., 1981; Foreman et al., 19791. 4. According to the convergence-facilitation hypothesis, the back- ground (resting) activity of pain projection neurons in the spinal cord that receive input from one somatic region is amplified (facili- tated) in the spinal cord by activity arising in nociceptors originat- ing in another region of the body. In this model, nociceptors producing the background activity originate in the region of perceived pain and tenderness; the nerve activity producing the facilitation origi- nates elsewhere, for example, at a myofascial trigger point. This convergence-facilitation mechanism is of clinical interest because one would expect that blocking sensory input in the reference zone
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ANATOMY AND PHYSIOLOGY OF PIN 131 with cold or a local anesthetic should provide temporary pain relief. One would not expect such relief according to the convergence- projection theory. Clinical experiments have demonstrated both kinds of responses. This phenomenon of referred pain can present a serious problem to both patients and physicians when it goes unrecognized. Because the source of the pain lies overlooked at a distant location, the lack of any demonstrable lesion at the site of pain and tenderness often leads to the suspicion that the pain has a strong psychological component. When health professionals insist that there is no reason for the pain, patients sometimes begin to wonder whether the pain is "all in their head." As is discussed in later chapters, this can exacerbate anxiety and other psychological reactions to the pain, is likely to frustrate both the doctor and the patient, and may lead to "doctor shopping" and inappropriate treatment. Pain Pathways in the Central Nervous System Primary afferent nociceptors transmit impulses into the spinal cord (or if they arise from the head, into the medulla oblongata of the brain stem). In the spinal cord, the primary afferent nociceptors terminate near second-order nerve cells in the dorsal horn of the gray matter (Willis, 19851. The primary afferent nociceptors release chemical transmitter substances from their spinal terminals. These transmit- ters activate the second-order pain-transmission cells. The identity of these transmitters has not been established, but candidates include small polypeptides such as substance P and somatostatin, as well as amino acids such as glutamic or aspartic acid. The axons of some of these second-order cells cross over to the opposite side of the spinal cord and project for long distances to the brain stem and thalamus. The pathway for pain transmission lies in the anterolateral quadrant of the spinal cord. Most of our information about 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 impairs pain sensation and that electrical stimulation of it produces pain (Cassinari and Pagni, 1969; White et al., 1950; Willis, 1985~. There are two major targets for ascending nociceptive axons in the anterolateral quadrant of the spinal cord: the thalamus and the medial reticular formation of the brain stem. Our knowledge is most extensive
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ANATOMY AND PHYSIOLOGY OF PIN 135 Akil, 19771. SPA has been demonstrated in a variety of animal species and in hundreds of patients. SPA can be elicited from well-clefined brain stem sites. A body of evidence now indicates that SPA is mediated by a discrete neuronal network running from the midbrain to the medulla and then to the spinal cord (Figure 7-1) (Basbaum and Fields, 1978, 19841. This descend- ing, pain-modulating pathway projects to regions of the spinal cord that contain pain-transmission neurons. Stimulation at brain stem sites that produce behavioral analgesia also selectively inhibits identified noci- ceptive spinothalamic tract neurons. This inhibition may underly the behavioral and clinical analgesia produced by brain stem stimulation. In addition to electrical stimulation, the analgesia network can be activated by morphine and other opiate analgesic drugs (Yaksh, 19781. The brain stem sites for SPA and the spinal cord are both sensitive to directly applied opiates. The weight of evidence indicates that opiates produce analgesia in part by activating these pain-modulating net- works. One of the most important discoveries in pain research was that the brain contains substances that have the same pharmacological prop- erties as plant-derived opiates and synthetic opioid drugs. These sub- stances, called endogenous opioid peptides, are present within nerve cells of the peripheral and central nervous systems (Palkovits, 19841. Of particular importance for our discussion is the presence in high concen- trations of these peptides in those brain stem sites implicated in pain suppression (Basbaum any Fields, 19841. As discussed in Chapter 9, these findings have led to some promising new psychopharmacological appli- cations. Studies of this endorphin-mediated analgesia system in laboratory animals have shown that it can be activated by a variety of stressful manipulations, including painful stimuli (Basbaum and Fields, 19841. Clinical studies indicate that it is activated after surgery and can have a significant analgesic effect (Fields and Levine, 1984; Levine et al., 1979~. The important point is that there is a well-defined network for controlling pain transmission. Current evidence indicates that this network accounts for some of the striking variability of reported pain intensity in different patients who have had apparently similar nox- ious stimuli. It has been suggested that failure of the pain-suppression system accounts for certain types of chronic pain states (Sicuteri et al., 1984; Terenius, 1985), but most pain experts consider this conclusion pre- mature. Much more work is needed to determine the extent to which this pain-modulating network operates on chronic pain.
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136 INFLUENCES ON PEN ED Ply BEHAVIOR PHYSIOLOGICAL PROCESSES THAT ENHANCE PAIN AND MAY LEAD TO CHRONICITY One of the most troublesome issues for patients, clinicians, and disability examiners is how to account for pain experiences that seem disproportionate to physical findings or objectively verifiable disease or injury. Although it is well known and well accepted that various psychosocial factors may enhance pain, the role of several physiologi- cal processes in amplifying and maintaining pain is perhaps not adequately taken into account when assessing patients' complaints. Sensitization Tissue damage initiates a variety of processes that sustain and amplify pain. With repeated stimuli, the thresholds of primary afferent nociceptors progressively decrease, so that normally innocuous stimuli become painful (Campbell et al., 1979; Gybels et al., 1979; LaMotte et al., 19833. For some primary afferent nociceptors, repeated noxious stimuli may induce continuous activity lasting for hours (National Academy of Sciences, 19851. 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 unbearably painful and a friendly slap on the back is excruciating. Other examples are the tenderness of a sprained ankle or an arthritic joint. In these situations it is painful to bear weight or even move the affected joint. Sensitization is a major feature of many and perhaps most clinically significant pains, but its cellular mechanism is unknown. Hyperactivity of the Sympathetic Nervous System: Reflex Sympathetic Dystrophy Patients with relatively minor injuries occasionally develop pain disproportionate to their injuries. Such pain often becomes progres- sively worse rather than following the usual course of lessening with time. It is important to stress that the pain persists well beyond the time when the original tissue-damaging process has ended. Further- more, the location of the pain may be quite different from the site of the precipitating pathology. In some of these patients hyperactivity of the sympathetic nervous system clearly plays a major role in sustaining the pain because selective blockade of the sympathetic outflow produces immediate and dramatic relief. The pain is usually accompanied by signs of sympa-
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ANATOMY AND PHYSIOLOGY OF PIN 137 For Input // ~ / Sympathetic Outflow / ~ / Lceptor Input ~ Motor Axons ,~/ FIGURE 7-4 Reflex activation of nociceptors in self-sustaining pain. There are two important reflex pathways for pain. The top loop illustrates the sympathetic component. Nociceptor input activates sympathetic reflexes, which activate or sensi- tize nociceptor terminals. The bottom loop illustrates the muscle contraction loop. Nociceptors induce muscle contraction, which, in some patients, activates muscle nociceptors that feed back into the same reflex to sustain muscle contraction and pain. thetic hyperactivity, such as a cold (vasoconstricted), sweaty limb. In addition, the skin may be hypersensitive to touch, as if the nociceptors were sensitized. With time, osteoporosis, arthritis, and muscle atrophy may set in and a permanent impairment of function may ensue. This condition, called reflex sympathetic dystrophy, usually responds to sympathetic blocks and physical therapy (De Takats, 1937; Livingston, 1943; Procacci et al., 19751. Physiological studies in animals indicate that the sympathetic outflow can induce discharge of primary afferent nociceptors. This is most prominent in damaged and regenerating afferents (Devor, 1984) but also occurs in undamaged, sensitized afferents (Roberts, 1986) (Figure 7-41. The reflex sympathetic dystrophy syndrome is relatively uncommon in its full-blown form, but sympathetic activity could be a common
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138 INFLUENCES ON P~N kD PMN BEHAVIOR factor in sustaining or amplifying pain that would ordinarily fade as the injured tissues heal. If this were the case, local signs of increased sympathetic activity could help provide objective evidence that a pain-producing pathological process is present. Muscle Contraction Nociceptor activity results in sustained contraction in muscles. In limbs, this muscle contraction produces flexion, a form of primitive withdrawal that is presumably a protective movement. Disease in the abdominal viscera (e.g., gut, liver) produces tension in the muscles of the abdominal wall. Pain arising from muscuToskeletal structures also produces contraction and tenderness in other muscles innervated by the same spinal segment (Head, 1893; Kellgren, 19381. There is some evidence that this spreading muscle contraction plays an important role in clinically significant pains. In patients with persistent pain it is common to find small areas in muscles that are quite tender. Pressure over these myofascial trigger points can repro- duce the patient's pain, and locally anesthetizing the points (or other manipulations of them) can give relief lasting days to months (Simons and Travell, 19831. The physiological basis of these trigger points is unknown, but the clinical evidence suggests that they are often involved In sustaining pain in the absence of ongoing tissue damage. Self-Sustaining Painful Processes: Livingston's "Vicious Circle" From the material just discussed, clinical observations clearly indi- cate that several processes are set in motion by tissue-~nmaging stimuli that activate nociceptors. In the peripheral tissues, pain- producing substances are released that sensitize the nociceptors so that normally innocuous stimuli can activate them. In addition, nociceptors themselves release factors such as substance P that in turn cause vasodilation, edema, and the release of sensitizing substances from nonneural cells (Lembeck, 19831. Presumably, these processes play a role in the activation of host defenses against infection or toxins. However, they do prolong and amplify pain. For example, a noxious stimulus to the skin would activate nociceptors. These nociceptors then activate spinal reflexes that pro- duce sustained muscle contraction with consequent activation of mus- cle nociceptors (Figure 7-41. In this case, the production of a second site of noxious input in muscle is due to a spinal reflex. In some cases (e.g., reflex sympathetic dystrophy), the nociceptive input also activates the
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ANATOMY AND PHYSIOLOGY OF PIN 139 sympathetic nervous system, which can feed back to the periphery to sensitize or even activate nociceptive primary afferents. Livingston (1943) was the first to emphasize the clinical importance of these positive feedback loops; that is, the pain produces muscle contraction and sympathetic outflow that in turn activate nociceptors, which produce more sympathetic outflow and muscle contraction, and so on (Figure 7-41. The point is that painful injuries set in motion secondary processes, not associated with tissue damage, that cause a prolonga- tion and spread of nociceptive input and may contribute to chronicity. These secondary processes set up foci of nociceptive input that are independent of the original site of injury. The pain acquires, so to speak, a life of its own. Although there is no question that these factors contribute to the pain in some cases, it is not clear what proportion of patients with chronic pain have it because of these factors. This would obviously be an important area for future research on chronic pain. Neuropathic Pain Damage to the peripheral or central nervous systems can produce chronic pain. For example, in some diseases that affect peripheral nerves, such as diabetes mellitus or alcohol toxicity, pain is very common. Traumatic injury to a peripheral nerve is rarely painful, but when it is, it may be dramatically so. CausaIgia (heat pain) is an example of pain induced by traumatic injury to a peripheral nerve. CausaIgia is a syndrome characterized by severe burning pain and signs of sympathetic nervous system hyperactivity (Mitchell, 1965; Roberts, 19869. Similarly, lesions of the central nervous system are rarely painful, but when they are, the pain is severe and resistant to treatment (Cassinari and Pagni, 1969; Riddoch, 19381. There are certain characteristics of neuropathic pain. It frequently begins several days to weeks after the injury that produces it and tends to worsen before stabilizing. It is usually accompanied by sensory abnormalities, including, paradoxically, deficits in pain sensation and painful hyperreactivity to ordinarily innocuous stimuli (Noordenbos, 1959; Ochoa, 19821. The mechanisms of neuropathic pain are not completely understood, but there are several factors that could contribute to them (Ochoa, 19821. Damaged primary adherents, presumably including nociceptors, acquire certain properties when they begin to regenerate. These include spontaneous activity, mechanical sensitivity, and sensitivity to sympathetic nervous system activity (Ochoa, 1982; Scadding, 19811.
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140 INFLUENCES ON PAIN AND PAIN BEHAVIOR Note that under these circumstances there can be pain either without any stimulus or with a very gentle, non-tissue-damaging stimulus. In addition to the peripheral sources of pain, damage to primary afferents produces changes in the pain-transmission neurons to which they project in the central nervous system. These cells become spon- taneously active and could be a source of pain, again in the absence of any noxious stimuli (Lombard and Larabi, 1983; Roberts, 19861. Trigeminal neuralgia and post-herpetic neuralgia are among the most common types of neuropathic pains. These conditions tend to strike older individuals, many of whom are retired. This may be why patients with pains that are obviously neuropathic account for only a small proportion of those who seek disability benefits. On the other hand, some patients with Tow back pain might have an element of nerve damage that adds to the painfulness of their problem as well as to its chronicity and resistance to conventional treatment. Further research on this issue is clearly needed, as are better methods for detecting injuries to nerves that innervate deep structures. Acute Versus Chronic Pain Is there any 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 patients' neurophysiology in a way that makes them somewhat different from people 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 be changes in the central pathways for pain transmission as well (Guilbaud et al., 1985; Kayser and Guilbaud, 19841. Experiments with rats in which nerves have been injured and observed over time have shown changes in the central nervous system, but it is not known how these changes relate to pain (Markus et al., 19841. People with recurrent headaches, arthritis, low back pain, angina, or low-grade malignancies may have had pain for years. The complaints, treatment, and patients' reactions may be different for each of these conditions. In some cases, psychological factors loom large. These factors are particularly prominent in patients with low back pain, facial pain, and headaches and seem to be more prominent the longer the pain persists. Psychological and somatic factors are not completely separate in maintaining pain. For example, stress and anxiety increase both muscle contraction and sympathetic outflow and would be expected to
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ANATOMY AND PHYSIOLOGY OF PIN 141 exacerbate any ongoing pain problem to which they contribute. Con- versely, any treatment that induces relaxation will reduce these factors and lessen pain. This may be one important connection between the psychosocial and the somatic factors that influence pain tolerance. POTENTIAL METHODS OF PHYSIOLOGICAL MONITORING In this chapter we have briefly surveyed the anatomy, physiology, and pharmacology of nociceptive transduction, transmission, and mod- ulation. These are objective and potentially observable phenomena initiated by stimuli that damage or threaten tissue. As we learn more about the transduction process, it may be feasible to measure the concentration of substances in regions of ongoing tissue damage that activate or sensitize primary afferent nociceptors. This could give an estimate of the level of stimulation of chemically sensitive nociceptors. The most promising technique at present is direct recording of the electrical activity in primary afferents. This is technically feasible and has been used in research, but it is not presently available for general clinical use. The monitoring of central pain transmission pathways is not prac- tical with the technology available. Although it is theoretically possi- ble, recording single units within the human nervous system requires a potentially dangerous surgical procedure. Multiunit, or evoked- potential, studies do not have the required specificity or spatial resolution to permit collecting meaningful data about clinical pain. It is technically possible to measure the chemicals released at spinal synapses by primary afferent nociceptors. If the concentration of such chemicals in the cerebrospinal fluid could be shown to correlate with either the activity of the primary afferent nociceptors or with the severity of clinical pain, this could provide evidence similar to that derived from recording the activity of the primary afferents. However, at the present time, the transmitter or transmitters for the primary afferent nociceptors are unknown. Another approach is to use positron emission tomography (PET) to monitor metabolic activity in central nervous system pain pathways. PET is a noninvasive scanning technique that can provide evidence of focal brain activity and of the concentration of certain chemicals. This technique requires that enough neurons be active in a large enough region for a long enough period of time to be detected. Because of the topographical organization of the cortex, this technique might be used to monitor the somatosensory cortex. A precise map of the body surface spreads over many millimeters of the cortex. Representation of the face
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142 INFLUENCES ON PIN ID PIN BEHAVIOR and hand on this map is very large, so it might be possible to detect ongoing activity produced by nociceptive input from these regions. At present, there is no evidence that such measurements show anything in patients with chronic pain. Indirect measures, such as those of sympathetic nervous system activity (skin temperature or skin resistance) or of muscle contraction in painful areas might be helpful in providing objective evidence of sustained nociceptive input. The measurement of skin temperature over extensive areas of the body surface, thermography, is being used clinically but is still not widely accepted as a reliable indicator of pain. Although they are simple, painless, and safe indicators of sympathetic function, indirect measures of painful input like thermography could be misreading. Sympathetic changes could be produced by nonspecific factors such as surprise or anxiety that do not involve pain. On the other hand, if the changes in sympathetic activity are highly localized, persistent, and consistent with the reported location of the patients' pain, routine evaluation of sympathetic function with techniques like thermography in patients with chronic pain might provide clues about the mechanisms sustaining the pain. Ultimately, the presence of pain in another individual is always inferred. Even if we could measure pain directly, such a measure would not be adequate to describe the experience of pain, and it is the experience that affects functioning, including the ability to work. REFERENCES Armstrong, D. Bradykinin, Kallidin and Kallikrein. Vol. 25 of Handbook of Exper~men- tal Pharmacology (Erdos, E.G., ed.). Berlin: Springer-Verlag, 1970. Barber, T.X. Toward a theory of pain: relief of chronic pain by prefrontal leucotomy, opiates, placebos, and hypnosis. Psychological Bulletin 56:430~60, 1959. Basbaum, A.I., and Fields, H.L. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annual Review of Neuroscience 7:309~338, 1984. Basbaum, A.I., and Fields, H.L. Endogenous pain control mechanisms: review and hypothesis. Annals of Neurology 4:451~62, 1978. Beecher, H.K. The Measurement of Subjective Responses. New York: Oxford University Press, 1959. Bisgaard, H., and Kristensen, J.K. Leukotriene B4 produces hyperalgesia in humans. Prostaglandins 30:791-797, 1985. Campbell, J.N., Meyer, R.A., and LaMotte, R.H. Sensitization of myelinated nociceptive adherents that innervate monkey hand. Journal ofNeurophysiology 42:166~1679, 1979. Cassinari, V., and Pagni, C.A. Central Pain, A Neurosz~rgical Survey. Cambridge, MA: Harvard University Press, 1969. Cervero, F. Visceral nociception: peripheral and central aspects of visceral nociceptive systems. Philosophical Transactions of the Royal Society of London, Series B 308:32~337, 1985.
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Representative terms from entire chapter: