Pain is a complex phenomenon that includes both sensory-discriminative and motivational-affective components.1 The sensory-discriminative component of pain depends on ascending projections of tracts (including the spinothalamic and trigeminothalamic tracts) to the cerebral cortex. Sensory processing at these higher levels results in the perception of the quality of pain (pricking, burning, aching), the location of the painful stimulus, and the intensity of the pain. The motivational-affective responses to painful stimuli include attention and arousal, somatic and autonomic reflexes, endocrine responses, and emotional changes. These account collectively for the unpleasant nature of painful stimuli.
The definition of pain as proposed by the International Association for the Study of Pain emphasizes the complex nature of pain as a physical, emotional, and psychological condition. It is recognized that pain does not necessarily correlate with the degree of tissue damage that is present. Failure to appreciate the complex factors that affect the experience of pain and reliance entirely on physical examination findings and laboratory tests may lead to misunderstanding and inadequate treatment of pain. Oversimplified anatomic concepts predispose to simplistic therapeutic interventions, such as neurectomy or rhizotomy, that may intensify pain or create new and often more distressing pain.
The nociceptive system is highly complex and adaptable. Sensitivity of most of its components can be reset by a variety of physiologic and pathologic conditions. Innovative medications are being developed that target the causes of pain by actions on pain transduction, transmission, interpretation, and modulation in both the peripheral nervous system (PNS) and the central nervous system (CNS).
Societal Impact of Pain
Pain is one of the most common reasons for visiting a physician. It is estimated that chronic pain may affect as many as 40% of the adult population.2 The prevalence of low back pain ranges from 8% to 37% and is particularly prominent in patients between 45 and 60 years of age. It is estimated that 40 million persons experience musculoskeletal pain conditions.3 Patients with malignant disease often experience increasing pain as their disease progresses. The costs to society related to chronic pain are immense with an estimate that the annual cost attributed to back pain, migraine headache, and arthritis of 40 billion dollars, excluding the costs of surgical procedures to treat pain and lost workdays.1
Neurobiology of Pain
The experience of pain involves a series of complex neurophysiologic processes, collectively termed nociception, with four distinct components: transduction, transmission, modulation, and perception. Transduction is the process by which a noxious stimulus (e.g., heat, cold, mechanical distortion) is converted to an electrical impulse in sensory nerve endings. Transmission is the conduction of these electrical impulses to the CNS with the major connections for these nerves being in the dorsal horn of the spinal cord and thalamus with projections to the cingulate, insular, and somatosensory cortices. Modulation of pain is the process of altering pain transmission. It is likely that both inhibitory and excitatory mechanisms modulate pain (nociceptive) impulse transmission in the PNS and CNS. Pain perception is thought to be mediated through the thalamus acting as the central relay station for incoming pain signals and the primary somatosensory cortex serving for discrimination of specific sensory experiences.1 Pain may occur in the absence of the occurrence of these four steps. For example, pain from trigeminal neuralgia occurs in the absence of transduction of a chemical stimulus at a nociceptor reflecting axonal discharges initiated at the site of a compressed or demyelinated nerve. Modulation of pain impulses may not occur if specific nervous system tracts are injured. For example, phantom limb pain occurs in the absence of nociception or nociceptors (pain receptors).
Peripheral Nerve Physiology of Pain
Nociceptors (Pain Receptors)
Nociceptors are a specialized class of primary afferents that respond to intense, noxious stimuli in skin, muscles, joints, viscera, and vasculature. Nociceptors are distinctive in that they typically respond to the multiple energy forms that produce injury (thermal, mechanical, and chemical stimuli) and provide information to the CNS regarding the location and intensity of noxious stimuli. In normal tissues, nociceptors are inactive until they are stimulated by sufficient energy to reach the stimulus (resting) threshold. Thus, nociceptors prevent random signal propagation (screening function) to the CNS for the interpretation of pain.
Specific types of nociceptors react to different types of stimuli. Generally, unmyelinated C-fiber afferents (conduction velocity <2 m per second) have receptive field of about 100 mm2 in human and signal the burning pain from intense heat stimuli applied to the glabrous skin as well as the pain from sustained pressure. Usually, the receptive field of a C-fiber afferent is about near 100 mm2 in human. Two types of myelinated A-fiber nociceptive afferents (conduction velocity >2 m per second) exist. Type I fibers (including Aβ and some Aδ fibers) are typically high-threshold mechanoreceptors and are usually responsive to heat and mechanical and chemical stimuli and may therefore be referred to as polymodal nociceptors. Type II fibers (Aδ fibers with lower conduction velocity of about 15 m per second) have no demonstrable response to mechanical stimuli and are thought to signal first pain sensation from heat stimuli. Pain from both chemical and cold stimuli is transduced by nociceptors whose pain signals are conducted toward the CNS via both myelinated and unmyelinated nerve fibers.
Sensitization of Nociceptors
Sensitization of nociceptors refers to the increased responsiveness of peripheral neurons responsible for pain transmission to heat, cold, mechanical, or chemical stimulation. Sensitization of nociceptors frequently occurs and is attributable to the release of inflammatory mediators and adaptation of signaling pathways in primary sensory neurons induced by noxious stimuli. In the majority of cases of acute inflammation, the process naturally resolves as tissues heal and peripheral sensitization diminishes and nociceptors return to their original resting threshold. Chronic pain, however, occurs if the conditions associated with inflammation do not resolve, resulting in sensitization of peripheral and central pain signaling pathway and increased pain sensations to normally painful stimuli (hyperalgesia) and the perception of pain sensations in response to normally nonpainful stimuli (allodynia).
Numerous endogenous chemicals, neurotransmitters, peptides (such as substance P, calcitonin gene–related peptide or CGRP, bradykinin), eicosanoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons, significantly contribute to the process of nociception and neuronal sensitization during peripheral inflammation and nerve injury.4 Most of these mediators are not constitutively stored but rather are synthesized de novo at the site of injury. The agents contribute to pain via two principal mechanisms. Some of these agents (e.g., bradykinin, protons, prostaglandin E2, purines, and cytokines) can directly activate nociceptors and/or induce the sensitization of the nociceptor response to painful stimuli, whereas others (e.g., serotonin, histamine, arachidonic acid metabolites, and cytokines) may activate the inflammatory cells, which in turn release cytokines, thereby leading to sensitization. The variety of chemical mediators released during inflammation can potentiate nociceptor responses (Fig. 6-1).
A variety of receptors and ion channels have been identified on dorsal root ganglion neurons and on peripheral terminals of nociceptive afferent fibers. These receptors, including purinergic,5 metabotropic glutamatergic, tachykinin,6 TRPV1 receptor and neurotrophic receptors, and ion channels (e.g., Nav1.8) in primary sensory neurons may also undergo significant adaptation after noxious stimuli, significantly lowering the firing thresholds of nociceptors and critically contributing to the induction and maintenance of neuronal sensitization, which manifest as allodynia and hyperalgesia.7
Primary Hyperalgesia and Secondary Hyperalgesia
In general, tissue injury and inflammation may activate a cascade of events leading to enhanced pain in response to a given noxious stimulus, termed hyperalgesia (e.g., a mild pinprick causing severe pain). Hyperalgesia is defined as a leftward shift of the stimulus–response function that relates magnitude of pain to stimulus intensity. Hyperalgesia is a consistent feature that appears following somatic and visceral tissue injury and inflammation. Hyperalgesia at the original site of injury is termed primary hyperalgesia, and hyperalgesia in the uninjured skin surrounding the injury is termed secondary hyperalgesia. Primary hyperalgesia is usually manifested as decreased pain threshold, increased response to suprathreshold stimuli, spontaneous pain, and expansion of receptive field. Whereas primary hyperalgesia is characterized by the presence of enhanced pain from heat and mechanical stimuli, secondary hyperalgesia is characterized by enhanced pain response to only mechanical stimuli. It is usually accepted that interaction between the proinflammatory mediators and their receptors in nociceptors leads to the induction of primary hyperalgesia, and sensitization of central neuronal circuits processing nociceptive information may account for the secondary hyperalgesia after tissue injury.
Central Nervous System Physiology
Pain transmission from peripheral nociceptors to the spinal cord and higher structures of the CNS is a dynamic process involving several pathways, numerous receptors, neurotransmitters, and secondary messengers. The spinal dorsal horn functions as a relay center for nociceptive and other sensory activity. The ascending pathways convey pain-related activity to the brainstem and forebrain in humans. Forebrain somatosensory cortex (SI and SII) accounts for the perception of sensory-discriminative of peripheral painful stimuli (i.e., the location and intensity of pain). Brain regions in the limbic cortex and thalamus account for the perception of motivational-affective components of pain. Descending projections originating from periaqueductal gray–rostral ventromedial medulla (PAG–RVM) system may either depress or facilitate the integration of painful information in the spinal dorsal horn (Fig. 6-2).
Dorsal Horn: The Relay Center for Nociception
Afferent fibers from peripheral nociceptors enter the spinal cord in the dorsal root, ascend or descend several segments in the Lissauer tract, and synapse with the dorsal horn neurons for the primary integration of peripheral nociceptive information. The dorsal horn contains four major neuronal components: the central terminals of primary afferent axons; intrinsic neurons, which terminate locally or extend into other spinal segments; projection neurons that pass rostrally in the white matter to reach various parts of the brain; and descending axons that extend caudally from several brain regions and terminate in the dorsal horn where they play an important role in modulating the integration of nociceptive information.
The central terminals of primary afferents occupy highly ordered spatial locations in the dorsal horn. The dorsal horn consists of six laminae (Fig. 6-3). Laminae I (marginal layer) and II (substantia gelatinosa) are often referred to as the superficial dorsal horn and are the primary regions where afferent C fibers synapse on second-order neurons. Lamina I contains both projection neurons and interneurons, and all of the neurons in lamina II are small interneurons. Lamina V is the site of second-order wide dynamic range (WDR) and nociceptive-specific (NS) neurons that receive input from nociceptive and nonnociceptive neurons. The NS neurons respond only to noxious stimuli in their peripheral environment, whereas WDR neurons respond to innocuous and noxious stimuli of many types, providing the neuronal mechanism for encoding of the intensity of stimuli. Both types of neurons are believed to be important in the perception of nociceptive information. Myelinated fibers innervating muscles and viscera terminate in laminae I, IV to VII, and the ventral horn, and the unmyelinated fibers from these organs mostly terminate in laminae I, II, and V as well as X.
Interneurons make up the great majority of the neuronal population throughout the dorsal horn. Many dorsal horn interneurons have axons that remain in the same lamina as the cell body, and they also give rise to axons that extend into other laminae. Interneurons in the dorsal horn can be divided into two main functional types: inhibitory cells, which use GABA and/or glycine as their principal transmitter, and excitatory glutamatergic cells. Interneurons in dorsal horn are important for integration and modulation of incoming nociceptive information.
Projection neurons with axons that project to the brain are present in relatively large numbers in lamina I and are scattered through the deeper part of the dorsal horn (laminae III to VI) and the ventral horn. Both the lamina I and the laminae III and IV projection neurons that express the NK1 receptor are heavily innervated by substance P–containing primary afferents. Those in lamina I, together with some of the projection cells in deeper laminae, have axons that cross the midline and ascend to a variety of supraspinal targets including the thalamus, the midbrain PAG, lateral parabrachial area of the pons, and various parts of the medullary reticular formation.
Two types of descending monoaminergic (serotoninergic and norepinephrinergic) axons project from the brain throughout the dorsal horn, mostly terminating in laminae I and II, and are involved in descending pain modulation. Serotoninergic axons in the spinal cord originate in the medullary raphe nuclei, whereas those that contain norepinephrine are derived from cells in the locus ceruleus and adjacent areas of the pons.
Gate Theory
The gate control theory of pain was first proposed by Ronald Melzack and Patrick Wall in 1965 to illustrate the neuronal network underlying pain modulation (a neurologic “gate”) in the spinal dorsal horn. According to this theory, painful information is projected to the supraspinal brain regions if the gate is open, whereas painful stimulus is not felt if the gate is closed by the simultaneous inhibitory impulses (Fig. 6-4). Here is a commonly used example to describe how this neuronal network modulates pain transmission. Usually, rubbing the skin of painful area seems to somehow relieve the pain associated with a bumped elbow. In this case, rubbing the skin activates large-diameter myelinated afferents (Aβ), which are “faster” than Aδ fibers or C fibers conveying painful information. These Aβ fibers deliver information about pressure and touch to the dorsal horn and override some of the pain messages (“closes the gate”) carried by the Ad and C fibers by activating the inhibitory interneurons in the dorsal horn. This hypothesis provided a practical theoretical basis for some approaches such as massage, transcutaneous nerve stimulation, and acupuncture to effectively treat pain in clinical patients.
Central Sensitization of Dorsal Neurons
Peripheral inflammation and nerve injury could alter the synaptic efficacy and induce central sensitization in the dorsal horn neurons and is considered a fundamental mechanism underlying the induction and maintenance of chronic pain. This central sensitization takes a number of different and distinct forms.
One form of central sensitization is wind-up of dorsal horn neurons, an activity-dependent progressive increase in the response of neurons over the course of a train of inputs. Repetitive discharge of primary afferent nociceptors results in a co-release with glutamate of peptidergic neuromodulators such as substance P and CGRP from the nociceptor central terminals in dorsal horn. Temporal summation of these peptide-mediated slow excitatory postsynaptic potentials (EPSPs) may activate NMDA receptor, by removing Mg2+ suppression of the channel, and increase the excitability of dorsal horn neurons. A behavioral correlate of wind-up can be produced in humans by repeated peripheral noxious heat or mechanical stimuli, where the pain increases with each successive stimulus even though the stimulus intensity does not change.8 After peripheral nerve injury, light touch can produce pain (allodynia) and repeated light touch can produce progressively increasing pain (summation).
The second form of central sensitization is a heterosynaptic activity-dependent plasticity that outlasts the initiating stimulus for tens of minutes. After the induction of this form of activity-dependent central sensitization by a brief (as short as 10 to 20 seconds), intense nociceptor-conditioning stimulus, normally, subliminal/subthreshold inputs begin to activate dorsal horn neurons as a result of an increase in synaptic efficacy. This NMDA receptor-mediated increase of synaptic efficacy occurs not only in those nociceptor central terminal synapses activated by the conditioning or initiating stimulus but also the synapses not activated by the conditioning or initiating stimulus (Fig. 6-5). For example, low-threshold sensory fibers activated by innocuous stimuli such as light touch can, after the induction of the heterosynaptic central sensitization, activate normally high–threshold nociceptive neurons, producing allodynia.
Other forms of central sensitization include long-term potentiation, transcription-dependent central sensitization, loss of inhibition, and rearrangement of synaptic contacts. The former refers to the fact that brief duration, high-frequency primary afferent stimulation does induce a potentiation of AMPA receptor–mediated responses at homosynapses on to second-order neurons. Peripheral noxious stimuli may produce transcriptional changes of several proteins critically involved in pain transmission (e.g., brain-derived neurotrophic factor [BDNF] and cytokines) in primary sensory and dorsal horn neurons, altering their function and facilitating pain transmission for prolonged periods. Activation of Aδ primary afferents may also induce long-term depression of transmission at primary afferent synapses on to inhibitory dorsal horn neurons, contributing to the augmentation of nociceptive information. Following a lesion to a peripheral nerve, the central axons of injured myelinated Aβ fibers sprout from their normal termination site in the deeper laminae (laminae II and IV) into lamina II of the dorsal horn, contributing to nerve injury–induced tactile allodynia. It is notable that accumulating evidence suggests that a critical role is played by microglia-mediated neuroinflammation in the dorsal horn plasticity that leads to neuropathic pain.9
Ascending Pathway for Pain Transmission
Ascending pathways from the spinal cord to sites in the brainstem and thalamus are important for the perception and integration of nociceptive information. The major ascending pathways important for pain include the spinothalamic tract (STT, direct projections to the thalamus), spinomedullary and spinobulbar projections (direct projections to homeostatic control regions in the medulla and brainstem), and spinohypothalamic tract (SHT, direct projections to the hypothalamus and ventral forebrain). Some indirect projections, such as the dorsal column system and the spinocervicothalamic pathway, also exist to forward nociceptive information to the forebrain through the brainstem. Similar pathways originating from the medulla trigeminal sensory nuclei also exist to process the nociceptive information from the facial structures.
Among these pathways, the STT is the most closely associated with pain, temperature, and itch sensation. Retrograde tracing studies demonstrate that the fibers traveling in the STT originate in the spinal dorsal horn neurons in lamina I (receiving input from small-diameter Aδ and C primary afferent fibers), laminae IV and V (receiving input primarily from large-diameter Aβ fibers from skin), and laminae VII and VIII (receiving convergent input from large-diameter skin and muscle, joint inputs). About 85% to 90% of neuronal cells with projections extending through the STT are found on the contralateral side, with 10% to 15% on the ipsilateral side. The axons of STT cells generally cross in the dorsal and ventral spinal commissures to reach the white matter of the contralateral spinal cord within one or two segments rostral to the cells of origin. The lateral STT originates predominantly from lamina I cells, and the anterior STT originates from deeper laminae V and VII cells. In the lateral STT, the axons from caudal body regions tend to be located more laterally (i.e., superficially) in the white matter, whereas those from rostral body regions are located more medially (closer to midline). The axons of STT terminate in several distinct regions of the thalamus.
Spinobulbar projections originate from similar neurons as those in the STT (i.e., laminae I, V, and VII in the spinal dorsal horn). Spinal projections to the medulla are bilateral, and those to the pons and mesencephalon have a contralateral dominance. Ascending spinobulbar projections terminate mainly in four major areas of the brainstem, including the regions of catecholamine cell groups (A1–A7), the parabrachial nucleus, PAG, and the brainstem reticular formation. Spinal projections to the brainstem are important for the integration of nociceptive activity with processes that subserve homeostasis and behavior.
The spinohypothalamic tract (SHT) originates bilaterally from cells in laminae I, V, VII, and X over the entire length of the spinal cord. The SHT axons often have connections with the contralateral diencephalon, decussate in the optic chiasm, and then descend ipsilaterally through the hypothalamus and as far as the brainstem. The SHT appears to be important for autonomic, neuroendocrine, and emotional aspects of pain.
Supraspinal Modulation of Nociception
Several brain areas have been recently defined using human brain imaging studies as key supraspinal regions involved in nociceptive perception. The most commonly activated regions during acute and chronic pain include SI, SII, anterior cingulate cortex (ACC), insular cortex (IC), prefrontal cortex, thalamus, and cerebellum (see Fig. 6-2). These brain regions form a cortical and subcortical network, which are critically involved in the formation of emotional aspects of pain and the central modulation of pain perception.
In primates, SI and SII receive noxious and innocuous somatosensory input from somatosensory thalamus.10 Cingulate cortex receives input from medial thalamic nuclei that contain nociceptive neurons, including nucleus parafascicularis and the ventrocaudal part of nucleus medialis dorsalis, as well as from lateral thalamic regions. The IC also receives direct thalamocortical nociceptive input in the primate. Prefrontal cortical regions are activated in a number of imaging studies of acute pain in normal subjects, but these activations are not as common as those in the other cortical regions described earlier. The prefrontal cortex receives input from ACC, but there is no evidence that it receives direct thalamocortical nociceptive input. Several nuclei in the thalamus receive nociceptive input from the dorsal horn, and the cerebellum also has reciprocal spinal connectivity. Activation of the hypothalamus during acute and chronic pain is likely mediated by direct spinohypothalamic projections. Other subcortical regions, such as the striatum, nucleus accumbens, amygdala, hypothalamus, and PAG are also reported to be active in human pain imaging studies.
In general, somatosensory cortices (e.g., SI and SII) are more important for the perception of sensory features (e.g., the location and intensity of pain), whereas limbic and paralimbic regions (e.g., ACC and IC) are more important for the emotional and motivational aspects of pain.11 Anesthetized humans, without conscious awareness of pain, still exhibit significant pain-evoked cerebellar activation, suggesting that pain-evoked cerebellar activity may be more important in regulation of afferent nociceptive activity than in the perception of pain.
Descending Pathways of Pain Modulation
The relationship between reported pain intensity and the peripheral stimulus that evokes the pain sensation depends on a host of variables, including the presence of other somatic stimuli and psychological factors such as arousal, attention, and expectation. Certain central mechanisms also exist to either impede or enhance the centripetal passage of nociceptive messages.12 Evidence demonstrates that descending pathways originating from certain supraspinal regions may concurrently promote and suppress nociceptive transmission through the dorsal horn, termed the descending inhibition pathway (DI) and the descending facilitation pathway (DF).12 Notably, there is no absolute, anatomic separation of substrates subserving these processes, and the stimulation of a single supraspinal structure may, via divergent actions of diverse transmitters and different receptor types, simultaneously trigger both DI and DF.
Electrical stimulation of the PAG and more rostral periventricular structures inhibits activity of nociceptive dorsal horn neurons and noxious stimulus-evoked reflexes and induces stimulation-evoked analgesia in rodents and humans. This establishes the PAG and the RVM regions of the brainstem as the critical brain regions underlying descending pain modulation (Fig. 6-6). PAG neurons receive direct or indirect inputs from several brain structures, including the amygdala, nucleus accumbens, hypothalamus and others, with ascending nociceptive afferents from the dorsal horn. The RVM includes the midline nucleus raphe magnus and the adjacent reticular formation that lies ventral to the nucleus reticularis gigantocellularis. The PAG and the adjacent nucleus cuneiformis are the major source of inputs to the RVM. The RVM receives input from serotonin-containing neurons of the dorsal raphe and neurotensinergic neurons of the PAG. The PAG–RVM connection is critical for pain modulation. The PAG projects only minimally to the spinal cord dorsal horn, and the pain-modulating action of the PAG on the spinal cord is relayed largely, if not exclusively, through the RVM.
Spinally projecting noradrenergic neurons of the pontine tegmentum contribute significantly to pain modulation. The locus ceruleus and the A5 and A7 noradrenergic cell groups are the major source of noradrenergic projections to the dorsal horn. Electrical stimulation in each of these regions produces behavioral analgesia and inhibition of dorsal horn neurons mediated by spinal α2-adrenergic receptors.
The PAG–RVM system also contributes to hyperalgesia and allodynia in inflammatory and neuropathic models. Data clearly demonstrate that the PAG–RVM system can facilitate nociception in some but not all models. Discovering how this system is recruited to either inhibit or facilitate nociception under different conditions is an important challenge for our future understanding of descending modulation.
Electrical stimulation of the RVM at different currents can produce inhibition or facilitation of dorsal horn nociceptive processing, suggesting that there are parallel inhibitory and facilitatory output pathways from the RVM to spinal cord. In fact, there are three distinct populations of neurons in the RVM: those that discharge beginning just prior to the occurrence of withdrawal from noxious heat (on cells), those that stop firing just prior to a withdrawal reflex (off cells), and those that show no consistent changes in activity when withdrawal reflexes occur (neutral cells; see Fig. 6-6).13 The on and off cells project specifically to laminae I, II, and V of the dorsal horn.13 Activation of RVM neurons could inhibit nociceptive transmission in the dorsal horn via either direct inhibition of projection neurons or activation of inhibitory interneurons in dorsal horn. It is now clear that off cells exert a net inhibitory effect on nociception, and on cells exert a net facilitatory effect on nociception. Neutral cells are serotonergic neurons, and projections of neutral cells tonically release serotonin at the level of the dorsal horn and modulate the action of other descending pain modulation systems via 5-HT3 receptor.12
It is also important to note that the PAG–RVM system serves as one of the major brain sites underlying opiate-induced analgesia. In the RVM, µ opioid receptors are primarily located on the on cells, and κ opioid receptor in the off cells. The µ opioid receptor agonists, including morphine and other opioid analgesics, produce a direct postsynaptic hyperpolarization by an increased K+ conductance in RVM on cells.14 These agents also act presynaptically to depress GABAergic synaptic transmission.15 Activation of κ opioid receptors exhibits bidirectional pain modulation, either analgesia or antagonism of µ opioid receptor–mediated analgesia.14,16 Chronic exposure to opiates induces emergence of functional δ opioid receptors in PAG–RVM system, which exhibit δ opioid receptor–mediated analgesia.17
Transition from Acute Pain to Chronic Pain
Acute pain is limited to the short-term, typically extending for days to weeks after injury. Acute pain provides an important protective mechanism, signaling the individual to protect the injured region from repeated injury, so that tissue healing can ensue. Under most circumstances, as tissue heals, the acute sensitization in the region surrounding the injury gradually subsides, and sensory thresholds revert to normal. Acute pain and the accompanying sensitization that accompany any injury do not typically persist after the initial injury has healed. In contrast, chronic pain is persistent pain that persists after all tissue healing appears to be complete and extends beyond the expected period of healing. In individuals with chronic pain, pain receptors continue to fire, even in the absence of tissue damage. There may no longer be a physically discernible tissue injury, yet the pain response persists. There is no clear delineation between when acute pain ends and chronic pain begins. Two common and practical cutoff points are often used, 3 months and 6 months after initial injury, as the likelihood that the pain will resolve diminishes with time and the likelihood that chronic pain will persist rises. Despite recent improvements in techniques for acute pain management, chronic pain persists in a significant proportion of patients following the most common surgical procedures.
While sensitization of peripheral and central nocisponsive neurons underlies the neurobiologic basis of the transition from acute pain to chronic pain, emerging evidence also suggests that an individual’s psychologic response after injury as well as noxious stimuli–induced epigenetic modification18,19 in the PNS and CNS are also critically involved in the induction and maintenance of chronic pain. Recent studies suggest that patients with subacute low back pain who are having negative affective experience (depression and poor adaptive skills) develop greater functional connectivity of nucleus accumbens with the prefrontal cortex, the brain regions processing emotion and reward, and these individuals are prone to develop persistent pain.18,20
Psychobiology of Pain
Unpleasant emotional experiences are an intrinsic and undesirable feature of painful experiences for the patients. Discomfort, fear of pain, and anxiety are the most common psychological responses observed in the patients with pain, although other adverse emotional responses, including depression, anger, disgust and guilt are not unusual in these patients.
Affective qualities of pain are transmitted and processed via the same pathways as those for the painful sensory transmission. Peripheral nociceptive information is delivered through spinoreticular pathways to diencephalic and telencephalic structures, including the medial thalamus, hypothalamus, amygdala, and limbic cortex. Central sensitization and adaptation of synaptic plasticity occur in these brain regions and contribute to the induction and maintenance of the emotional distress that often accompanies pain.11
Intrinsic interactions occur between the sensory and affective components of pain. Although the affective qualities of the painful experience vary from individual to individual, most patients experiencing acute or chronic pain display substantial emotional, behavioral, or social abnormalities. While these affective symptoms may gradually wane, a substantial proportion of patients with chronic pain experience debilitating depression, anxiety, cognitive deficits such as memory impairment, and other negative psychological components of pain. Similarly, emerging evidence suggests that severe emotional distress can trigger new pain or exacerbate ongoing pain in the patients with previous painful experiences.
Some Specific Types of Pain
Neuropathic Pain
Neuropathic pain is pain that persists after tissue injury has healed and is characterized by reduced sensory and nociceptive thresholds (allodynia and hyperalgesia). Injury of peripheral nerves by trauma, surgery, or diseases (e.g., diabetes) frequently results in the development of neuropathic pain. Cancer patients are at increased risk of neuropathic pain caused by radiotherapy or a variety of chemotherapeutic agents. Although acute and inflammatory pain are usually considered as an adaptive process of the pain system to provide warning and protection, neuropathic pain actually reflects a maladaptive (pathophysiologic) function of a damaged pain system. In many patients, neuropathic pain persists throughout life and negatively affects physical, emotional, and social quality of life.19 Current treatments for neuropathic pain are only modestly effective, providing some symptomatic treatment for neuropathic pain. Opioids, gabapentin, amitriptyline, and medicinal cannabis preparations have been tried and shown to be only marginally effective.21–23 The pathophysiologic processes that lead to neuropathic pain has the hallmarks of a neuroinflammatory response following innate immune system activation. Toll-like receptors 2 and 4 (TLR2 and TLR4) found on microglia appear to trigger glial activation, initiating proinflammatory and signal transduction pathways24,25 that lead to the production of proinflammatory cytokines. Established mechanical allodynia can be reversed by intrathecally delivered TLR4 receptor antagonists,26 preventing transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and TNF-α (tumor necrosis factor-alpha) overproduction in the spinal cord after sciatic nerve injury.27 Central cannabinoid receptor type 2 (CB2) appears to play a protective role and administration of a CB2 receptor agonist can blunt the neuroinflammatory response and prevent peripheral neuropathy through interference with specific signaling pathways.28,29
The common pathologic features of the neural damage include segmental abnormal myelination/demyelination and axonopathy, ranging from metabolic and axoplasmic transport deficits to frank transection of the axon (axotomy). After nerve injury occurs, the proximal stump of the axon seals off and forms a terminal swelling or “end bulb,” and numerous fine processes (“sprouts”) start to grow out from the end bulb within 1 or 2 days. These regenerating sprouts normally elongate within their original endoneurial tube and restore the normal sensation in appropriate peripheral targets. However, when the forward growth of the axon is blocked, such as after limb amputation, end bulbs and aborted sprouts form a tangled mass at the nerve end, a “nerve-end neuroma.” Usually, the ectopic firing generated in end bulb and sprouts within the neuroma, as well as the cell bodies in DRG, significantly contribute to the nociceptive hypersensitivity and ectopic mechosensitivity that follow nerve injury.
Visceral Pain
While somatic pain is easily localized and characterized by distinct sensations, visceral pain is diffuse and poorly localized, typically referred to somatic sites (e.g., muscle and skin), and it is usually associated with stronger emotional and autonomic reactions. Visceral pain is often produced by stimuli different from those adequate for activation of somatic nociceptors. These features may be attributable to dual nerve innervation and the unique structure of visceral receptive endings.
Among all tissues in the body, the viscera are unique in that each organ receives innervation from two sets of nerves, either vagal and spinal nerves or pelvic and spinal nerves, and the visceral afferent innervation is sparse relative to somatic innervation. Spinal visceral afferent fibers have their cell bodies in dorsal root ganglia (DRG) and terminate in the spinal dorsal horn. The central termination of visceral afferents synapse spinal neurons in laminae I, II, V, and X over several segments and deliver the visceral sensory information through the contralateral spinothalamic tract or ipsilateral dorsal column to supraspinal brain sites. These spinal neurons also receive convergent input from somatic and other visceral structures, providing the structural basis for referred pain; for example, the left-sided jaw and arm pain that accompany myocardial ischemia are mediated by convergence of visceral and somatic sensory fields. Another nervous structure conveying pain information from organs in the thoracic and abdominal cavities is the vagus nerve, which has cell bodies in the nodose ganglion and central terminals in the nucleus tractus solitarii. The vagus afferent innervation plays an important role in the prominent autonomic and emotional reactions in visceral diseases associated with pain (Fig. 6-7). The majority of visceral afferent fibers are thinly myelinated Aδ fibers or unmyelinated C fibers with unencapsulated free nerve endings, with a small number of Aβ fibers associated with Pacinian corpuscles in the mesentery. Best characterized mechanosensitive endings in the viscera are the intraganglionic laminar endings (IGLEs) and intramuscular arrays associated with vagal afferent fibers that innervate the stomach. Most of these visceral sensory neurons contain substance P and/or CGRP, and they also express the high-affinity nerve growth factor receptor TrkA. These biomarkers significantly increase and the nociceptors become sensitized during visceral inflammation. Unlike noxious stimuli to induce somatic pain, many damaging stimuli (cutting, burning, clamping) produce no pain when applied to visceral structures. Activation of visceral nociceptors is generally induced by ischemia, stretching of ligamentous attachments, spasm of smooth muscles, or distension of hollow structures such as the gallbladder, common bile duct, or ureter. These stimuli occur in many visceral pathologic processes, and the pain they induce may serve a survival function by promoting immobility.
Complex Regional Pain Syndromes
The International Association for the Study of Pain (IASP) Classification of Chronic Pain defines complex regional pain syndrome (CRPS) as “a variety of painful conditions following injury which appears regionally having a distal predominance of abnormal findings, exceeding in both magnitude and duration the expected clinical course of the inciting event often resulting in significant impairment of motor function, and showing variable progression over time.” These chronic pain syndromes have different clinical features including spontaneous pain, allodynia, hyperalgesia, edema, autonomic abnormalities, active and passive movement disorders, and trophic changes of skin and subcutaneous tissues. Two types of CRPS, type I (reflex sympathetic dystrophy) and type II (causalgia), by the presence of a major identifiable nerve injury in the CRPS II and the absence of a major nerve injury in CRPS I. CRPS I develops more often than CRPS II, and females are more often affected than males (2:1 to 4:1). The incidence of CRPS I is 1% to 2% after fractures, 12% after brain lesions, and 5% after myocardial infarction, and the incidence of CRPS II in peripheral nerve injury varies from 2% to 14% in different series, with a mean around 4%.
The following IASP clinical criteria are applied to diagnose the CRPS. CRPS type I: (a) type I is a syndrome that develops after an initiating noxious event; (b) spontaneous pain or allodynia/hyperalgesia occurs, is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event; (c) there is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event; and (d) this diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction. CRPS type II: (a) type II is a syndrome that develops after nerve injury; spontaneous pain or allodynia/hyperalgesia occurs and is not necessarily limited to the territory of the injured nerve; (b) there is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event; and (c) this diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.
The mechanism underlying the pathogenesis of CRPS remains unclear, although it is recognized that CRPS is a neurologic disease including the autonomic, sensory, and motor systems as well as cortical areas involved in the processing of cognitive and affective information, and the inflammatory component appears to be particularly important in the acute phase of the disease. Effective, evidence-based treatment regimens for CRPS are lacking.
Pain in Neonate and Infant
Accumulating evidence overrides the outdated thought that young children do not feel pain due to the immaturity of the PNS and CNS. Reflex responses to somatic stimuli begin at 15 days (E15, where gestation is 21.5 days) in the rat fetus, and the human fetus develops pain perception by 23 weeks of gestation. Postnatal maturity of pain behavior develops quickly after birth. Usually, newborns and young children have significantly lower pain thresholds and exaggerated pain responses compared to adults.30 Some clinical studies reveal the long-term effects of neonatal pain experience, which is affected by several confounding factors such as gestational age at birth, length of intensive care stay, intensity of the stimulus and parenting style. Toddlers and adolescents exhibit long-lasting hypersensitivity to painful stimuli after painful experiences as neonates. These observations highlight the clinical importance of optimal management of pain in neonates and infants.
Embryologic Origin and Localization of Pain
The position in the spinal cord to which visceral afferent fibers pass for each organ depends on the segment (dermatome) of the body from which the organ developed embryologically. This explains the phenomenon pain that is referred to a site distant from the tissue causing the pain (Fig. 6-8). For example, the heart originates in the neck and upper thorax such that visceral afferents enter the spinal cord at C3 to C5. As a result, the pain of myocardial ischemia is referred to the neck and arm. The gallbladder originates from the ninth thoracic segment, so visceral afferents from the gallbladder enter the spinal cord at T9. Skeletal muscle spasm caused by damage in adjacent tissues may also be a cause of referred pain. For example, pain from the ureter can cause reflex spasm of the lumbar muscles.
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