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Pain Pathways Anatomy Ascending Pathways Endorphin System
Pain propagation is initiated with activation of nociceptors, distributed within skin, muscle, joints, and viscera. These receptors include small-diameter Aδ and C-fiber free nerve endings representing distal primary afferent neurons. Cutaneous Aδ fibers (myelinated) mediate sharp sensation of first-phase or acute pain known to trigger withdrawal responses. These include two fiber groups; first are high-threshold mechanoreceptors fibers , responding to mechanical stimuli of high intensity and, after sensitization, to noxious heat. Mechanothermal receptors for extreme (i.e., noxious) heat and cold sensation comprise the second group of fibers. Once sensitized, these receptors are activated by mechanical stimuli at non-noxious thresholds.
C-type fibers (unmyelinated) slowly propagate dull, burning (secondary) pain sensation information. Some C fibers are modality-specific and respond only to thermal, mechanical, or chemical noxious stimuli. However, the majority of C fibers are polymodal, which means that they respond to both thermal and mechanical noxious stimuli, as well as to chemical algesiogenic substances (e.g., potassium ions, prostaglandins, substance P, and histamine). A unique C-fiber subtype responds to high-intensity thermal stimuli and also mediates flare responses after tissue damage. Some C-type nociceptors, designated silent receptors , are primarily activated by inflammation.
The primary afferent fibers travel through dorsal nerve roots entering the dorsal horn of the spinal cord, where they divide in a “ T ” pattern traveling two to three spinal segments within the Lissauer tract in both rostral and caudal directions, and sending collateral projections to the gray matter along the entire four- to six-segment length, thus transmitting pain signals over a broad spinal cord area.
Both myelinated and unmyelinated primary afferent fibers project predominantly to the superficial laminae of the dorsal horn. Although there is considerable overlap in the projection of fibers, signaling innocuous and noxious stimuli, there exists some degree of functional segregation at the postsynaptic level in the superficial laminae. Dorsal horn neurons are classified into three distinct groups. The specific nociceptive neurons that respond exclusively to noxious stimuli are found in Rexed laminae I, II, V, and VI. Their receptive fields in lamina I are punctiform and display somatotopic organization.
Lamina I neurons are classified into several modality-selective classes, relaying information from particular subsets of small-diameter fibers and relating the current physiologic status of body tissues. The two nociceptive cell types, nociceptive-specific (NS) and polymodal nociceptive (HPC, for heat, pinch, and cold) have different characteristics. NS neurons receive mainly Aδ inputs associated with first-pain, and relay information about noxious stimuli localization and physical quality. HPC cells receive polymodal C-nociceptor information and are associated with second pain. Lamina I cells relate current physiologic conditions of all body tissues and regulate spinal cord excitability, and therefore pain behavior, through the activation of descending inhibitory and excitatory pathways from the brainstem.
Lamina V neurons are large cells with dendrites extending across the dorsal horn, receiving myelinated primary afferent input from Aβ, Aδ, and C fibers. According to gate control theory, this fiber group is important for segmental suppression of pain; however, their inhibitory role is not yet confirmed. Almost all of lamina V consists of wide dynamic range (WDR) cells, which have large receptive fields and high-frequency ongoing discharges. WDR neurons demonstrate graded responses to pressure and noxious stimuli, including heat, cold, and deep and visceral stimulation. Their activity represents integration of all dorsal horn afferent inputs. In contrast to lamina I neurons, WDR cells are not somatotopically organized; their complex excitatory and inhibitory receptive fields are musculotopically organized. Their main characteristic is to code stimulus intensity; they demonstrate increasing frequencies of response from innocuous to noxious stimulation.
Intrinsic dorsal horn neurons promote interaction of afferent and efferent nociceptive stimuli and are also responsible for their transfer to supraspinal structures. These are classified as (1) projection neurons directly transmitting information to supraspinal centers, (2) intersegmental propriospinal neurons integrating several spinal levels, and (3) interneurons having inhibitory or excitatory features. Nociceptive projection neurons relay information to various brainstem and diencephalon regions, including the thalamus, periaqueductal gray, bulbar reticular formation, and limbic structures within the hypothalamus, amygdala, and other sites. There is also a visceral nociceptive pathway within the postsynaptic posterior column pathway.
The spinothalamic tract (STT) mediates sensations of pain, cold, warmth, and touch. This pathway originates from WDR, SN, and non-nociceptive dorsal horn neurons in laminae I, II, and deeper lamina V. Most spinothalamic tract axons decussate transversely through the anterior white commissure of the spinal cord and ascend through the contralateral anterolateral funiculus. Passing through the brainstem, the spinothalamic tract sends collateral projections to the medullary, pontine, and midbrain reticular formation, including gigantocellularis and paragigantocellularis nuclei and periaqueductal gray matter. These are probably responsible for descending suppressor system activation, as well as behavioral and neurovegetative responses to pain. Three spinothalamic tract afferent forms are recognized, including a monosynaptic neospinothalamic pathway (anterior spinothalamic tract) that directly projects to lateral complex thalamic nuclei involved in sensory-discriminative pain components. Another is a multisynaptic paleospinothalamic pathway , (dorsal spinothalamic tract) projecting to posterior medial and intralaminar complex thalamic nuclei involved in the motivational-affective aspects of pain. Lastly, there is a monosynaptic spinothalamic pathway projecting directly to thalamic medial central nucleus that is related to affective components of pain sensation.
The thalamus is the main relay structure for sensory information destined for the cortex; it is involved in reception, integration, and transfer of nociceptive potentials. WDR neurons project to the ventroposterolateral (VPL) and ventroposteromedial (VPM) nuclei . SN neurons project to the ventroposteroinferior (VPI) nucleus, considered the main somatosensory relay. It receives both noxious and innocuous information of cutaneous, muscular, and articular origin. This nucleus has numerous interconnections with the primary somatosensory (SI) cortex. The VPI participates in the processing of visceral pain, occurring through the postsynaptic dorsal column pathway with nucleus gracilis projections.
The VPM nucleus is likewise involved in sensory-discriminative aspects of thermal, mechanical, and tactile information. Owing to its projections to the prefrontal cortex, the convergence of fibers arising from the parabrachial region within the lateral pons at the locus ceruleus level, as well as to amygdala, hypothalamic, and periaqueductal gray interconnections, the VPM nucleus is likely involved with emotional pain, as well as psychomotor and autonomic reactions to painful stimuli. Posterior division of the ventromedial nucleus (VmPO) and posterior nucleus (PO) are essential parts of the medial nociceptive system establishing insular and cingular cortex connections involved in affective-cognitive aspects of pain. Specific spinothalamic tract projections, originating from lamina I, suggest that these nuclei are noxious information integration centers, especially for cases of freezing and visceral sensations.
The thalamus medial complex receives afferent input from laminae I and V of the spinothalamic tract, interconnecting with the striatum and the cerebellum. This is responsible for the control of attention and motor responses, suggesting that this area may be involved in escape behavior in the presence of harmful stimuli.
Ultimately the nociceptive signal is relayed from the thalamus to a variety of cortical regions. Two systems of nociceptive cortical projection are commonly distinguished: the lateral and medial systems. There are three important cortical regions: primary somatosensory cortex (SI), secondary somatosensory cortex (SII), and the anterior cingulate cortex. The lateral nociceptive system participates directly in the sensory-discriminative ascription of nociception involving specific thalamic nuclei, projecting to SN and WDR neurons of the SI and SII cortices. SN neurons are associated with topographic localization of peripheral stimuli, whereas WDR neurons code the intensity of these stimuli. Nociceptive neurons in the SII cortex code the painful stimulus in temporal terms. Both SI and SII cortices have connections with the posteroparietal area and the insula, responsible for somatosensory input association with learning and memory. This pathway is crucial to assessment of the stimuli features and behavioral decisions in relation to the prefrontal cortex functions. Conversely, the medial nociceptive system has more diffuse projections from the medial thalamus to SI and SII, and limbic structures, such as the insula and the anterior cingulate cortex. Accordingly, it is predominantly responsible for the motivational-affective component of pain.
The insula relays information from the lateral nociceptive system to the limbic system, mainly via the amygdala and prefrontal cortex associated with the emotional and affective component and with memory integral to the painful experience. The anterior cingulate cortex coordinates inputs from parietal areas with frontal cortical regions, integrating the perception of threat with the appropriate pain behavior.
Descending Nociceptive Pathways and Neurochemical Foundations of Descending Pain Modulation
Descending Nociceptive Pathways
Descending control of spinal nociception arises from various brain areas and is pivotal in determining the experience of pain, both acute and chronic. Several central nervous system areas exert a top-down modulation of nociceptive processing. Projections from prefrontal, anterior cingulate, and insular cortices, as well as hypothalamus and amygdala to the brainstem pain modulatory system, support the notion of emotional and affective regulation of pain transmission. Attention, anticipation, control over pain, and religious beliefs affect pain perception, supporting the importance of the anterior cingulate cortex and frontal lobes in modulation of nociceptive processing.
The current model of descending pain modulation involves both inhibitory and facilitatory influences on spinal nociceptive transmission. The balance between inhibition and facilitation is dependent on different behavioral, emotional, and pathologic conditions. Intense stress or fear is associated with decreased response to pain, whereas inflammation, nerve injury, or sickness is associated with hyperalgesia that partially can be ascribed to descending facilitatory mechanisms. Several studies suggest that descending facilitatory systems are also activated by safety signals that follow an aversive event. In addition, descending facilitation of spinal nociception contributes to central sensitization and development of secondary hyperalgesia. Finally, hyperalgesia encountered during acute opioid abstinence also entails descending nociceptive facilitation from the rostral ventromedial medulla.
A number of supraspinal sites activated by nociceptive input contribute to central modulation of pain. The most prominent ones include periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). The effects of descending modulation are exerted in the spinal dorsal horn on the synapse between the primary afferent and projection neurons or on interneurons that synapse with projection neurons, by inhibiting the release of neurotransmitter from primary afferent fibers or by inhibiting the function of neurotransmitter receptors on the postsynaptic neuron.
In awake, behaving animals, anterolateral periaqueductal gray (PAG) stimulation leads to immobility, sympathoinhibition, and analgesia as well as inhibition of nociceptive dorsal horn neurons, including spinothalamic tract cells. The PAG contains a large number of neurons. Local injection of opioids, nonspecific enkephalin, substance P, and gamma-aminobutyric acid (GABA)ergic excitants or neuropeptides into the PAG produces analgesia in animals. Excitatory pathways projecting from the PAG to the brainstem are subject to inhibitory control by GABAergic inhibitory neurons within the PAG. Analgesic opioids and cannabinoids relieve GABAergic control and thus induce analgesia. The PAG is significantly interconnected with the hypothalamus and limbic forebrain structures, including the amygdala. This suggests that cognitive and emotional aspects influence ascending nociceptive input, further modulating the resultant experience of pain.
Major brainstem inputs to the PAG originate from the nucleus cuneiformis, the locus ceruleus, the pontomedullary reticular formation, and other catecholaminergic nuclei .
Major descending projections from the anterolateral PAG are to the rostral ventromedial medulla, including the nucleus raphe magnus and adjacent reticular formation . The PAG pain-modulating action is relayed almost exclusively through the RVM that, in turn, sends bilateral descending projections through posterolateral spinal funiculi terminating within the spinal dorsal horn. The RVM is a functional term describing the midline pontomedullary area in which opioid injection or electrical stimulation produces antinociception , that is, analgesia. It includes the nucleus raphe magnus and adjacent reticular formation and projects diffusely to dorsal horn laminae important in nociceptive processing, including superficial layers and deep dorsal horn.
With increasing understanding of RVM neuronal physiology, it is recognized that this area is central to the mediation of the bidirectional control of nociception. It receives projections from serotonin-containing neurons of the dorsal raphe, neurotensinergic neurons of the PAG, and limbic and prelimbic cortex, including the anterior insula. Nonselective stimulation or inactivation of RVM neurons can either suppress or facilitate nociception, depending on the functional background. This suggests that there are parallel inhibitory and facilitatory output pathways from the RVM to the spinal cord. Adjacent neurons are simultaneously under facilitatory and inhibitory control from supraspinal structures. The equilibrium between inhibition and facilitation determines the net effect of descending modulation on nociceptive transmission.
The RVM includes three distinct types of neurons: (1) neurons that begin discharging just before the withdrawal from noxious heat, entering a period of activity (“ ON-cells ”), (2) neurons that stop discharging before the withdrawal reflex, entering a period of silence (“OFF-cells”), and (3) neurons that do not demonstrate consistent changes in activity when withdrawal reflex occurs (“neutral cells”) . ON and OFF cells send projections specifically to laminae I, II, and V of the dorsal horn. Activation of OFF cells produces behavioral antinociception, and is required for the analgesic opioid effect. In contrast, direct, selective activation of ON cells produces hyperalgesia; their discharge is associated with enhanced nociception. Thus OFF cells exert a net inhibitory effect on nociception, whereas the ON cells play a facilitatory role in the descending modulation of pain.
Neutral cells' role in pain modulation is unexplained. One theory is that neutral cells are recruited to become ON or OFF cells during development of chronic pain states, which is supported by wide variations of ON and OFF cells excitability under basal conditions. At least some neutral cells are serotonergic. Considering the importance of serotonin in nociceptive modulation, this suggests that neutral cells may be involved in the descending control of pain transmission.
The locus ceruleus and the A5 and A7 noradrenergic cell groups of the posterolateral pons are the main source of noradrenergic input to the dorsal horn. These regions send bilateral projections that primarily descend to contralateral laminae I, II, and V of the spinal dorsal horn, exerting an antinociceptive effect. The PAG sends input to the locus ceruleus and the A7 region. RVM neurons containing substance P or enkephalin also send input to A7. Consequently, the posterolateral pontine tegmentum provides a corresponding pathway for the PAG and RVM to provide descending nociception control over the spinal dorsal horn. Posterolateral pontine systems may also provide cortical control of spinal pain transmission. The anterior insular cortex has locus coeruleus and RVM connections, suggesting that inhibition of the insular outflow disinhibits noradrenergic neurons of the locus ceruleus.
Neurochemical Foundations of Descending Pain Modulation
Opioids have long been considered the archetypical analgesics, with endogenous opioids (“enkephalins”) believed to play a pivotal role in the modulation of pain transmission. Recently, however, it has been shown that the monoaminergic pathways mediate modulation of nociceptive processing. Monoaminergic systems include serotonergic, noradrenergic, and dopaminergic neurons that elicit either antinociceptive or pronociceptive effects, depending on the type of receptor involved and its location. Monoaminergic modulation entails complex interplay between primary nociceptive afferents, dorsal horn projection neurons, local interneurons, and glial cells.
The RVM is the major source of serotonergic input to the dorsal horn; it is the final common output for descending influences from rostral brain regions projecting to the superficial and deep dorsal horn. The PAG-RVM serotonergic pathway is considered to be the major endogenous pain modulatory system and the main target of supraspinal opioid analgesia. Serotonergic neurons can exert antinociceptive action (in response to chemical stimuli and neurogenic inflammation) as well as pronociceptive action (in response to mechanical stimuli), depending on the activation of different serotonergic receptors.
Noradrenergic neurons originating from locus ceruleus and A5 and A7 pontine tegmentum groups provide inhibition of nociceptive input via presynaptic alpha-2 receptors . In this case, noradrenergic modulation relies upon volume transmission, in contrast to the serotonergic system mediating punctate synaptic transmission. The effect of this noradrenergic system is essentially an extrasynaptic spread of neuroactive substances that may be involved in late and long-lasting changes of a group of neurons. The analgesic effects mediated through presynaptic alpha-2 receptors involve presynaptic inhibition in primary afferents, postsynaptic inhibition of projection neurons, as well as a complex interplay with opioid and adenosine antinociceptive systems.
Dopaminergic pathways originate mainly from A11 neurons of the periventricular posterior thalamus . Their activation results in diminished response to noxious stimuli mediated by D2 receptors, with concomitant inhibition of neurotransmitter release from primary afferents. Possibly, endogenous opioids provide potentiating effects that develop from. Conversely, D1 receptor activation engenders facilitated nociception transmission , both directly and by opioid antagonism. The possible mechanism of action for dopamine may rely on local dopamine concentration; low levels activate antinociceptive D2 receptors, and high levels elicit pronociceptive effects via D1 receptors.
Nociceptive Processing and Central Nervous System Correlates of Pain
Neuropathic Pain
The International Association for the Study of Pain defines this as pain initiated or caused by a primary lesion or dysfunction within the nervous system. The term “dysfunction” may be rather vague, and perhaps using a lesion-based definition is more accurate. Peripheral neuropathic pain results from a diverse array of insults to the peripheral nervous system (PNS) variously caused by mechanical trauma, metabolic diseases (i.e., diabetes mellitus), infection (i.e., herpes zoster), tumor invasion, or neurotoxic chemicals. Among the associated risk factors for neuropathic pain, gender, age, anatomic site of the injury, and even the severity of acute postoperative pain are cited. Epidemiologic studies identify the prevalence of neuropathic pain to be as high as 5%.
Neural injury triggers a range of processes affecting primary afferent receptors, their axons and cell bodies, as well as unleashing a complex immune response in central neurons and glial cells. Some of these processes facilitate healing and normative repair, for example, removal of cell and myelin debris, recruitment of antiapoptotic strategies, induction of axonal growth and sprouting, synaptic remodeling, and remyelination. In contrast, animal neurophysiologic studies demonstrate that some of these secondary effects have a maladaptive effect. Other well-characterized effects leading to chronic pain include central sensitization, ectopic impulse generation, reduced central inhibition, neuronal loss, and glial scarring.
Peripheral Sensitization
Various signaling molecules, including cytokines, chemokines, neurotransmitters, neurotrophic factors, and excess protons released due to tissue injury and inflammation, directly activate or sensitize nociceptors. Increased expression of ion channels involved in pain transmission is an important mechanism leading to development of peripheral sensitization. Peripheral nerve injury leads to increased expression of specific voltage-gated sodium (Nav) channels and transient receptor potential vanilloid receptor 1 (TRPV1) cation channels in the primary afferent terminals, in axonal sprouts at the lesion site, demyelinated areas, and adjacent unharmed nociceptors in the site of injury. These channel changes are significant for the expression of neuropathic pain.
Peripheral sensitization has several important ramifications. It reduces the threshold for nociceptor activation, causes primary hyperalgesia (augmentation of normally noxious stimuli), and elicits spontaneous depolarization in primary afferent fibers (ectopic activity). Concomitantly, the peripheral injury enables these neurotrophic factors to migrate in a retrograde direction, thus affecting dorsal root ganglion and dorsal horn cells.
Ectopic Impulse Generation
The persistence of an unpleasant sensory and emotional experience in the absence of an identifiable ongoing stimulus is a characteristic feature of neuropathic pain. This spontaneous pain occurs as a result of ectopic action potential generation in primary afferent neurons. It may originate both from ectopic activity in nociceptors and from low-threshold large myelinated afferents due to central sensitization and altered connectivity in the spinal cord. Ectopic discharges originating in the cell body of injured primary afferents may cause antidromic stimulation, the release of mediators, and neurogenic inflammation at the periphery. Ectopic impulses can also generate along neuromas and from the sprouting of sympathetic efferents, forming “baskets” around dorsal root ganglion (DRG) cells. Sympathetic sensory coupling is believed to play an important role in the pathophysiology of inflammatory pain, complex regional pain syndrome (CRPS), diabetic neuropathy, postherpetic neuralgia, phantom limb sensations, and other conditions. Also deafferentation (loss of normal afferent input) can lead to sensitization and ectopic discharges in spinal cord or thalamic neurons.
Voltage-gated sodium channels are important influences on the generation of ectopic activity; their role in the pathogenesis of neuropathic pain is supported by the reversal of nociceptive effects by nonselective sodium channel blockers such as local anesthetics. Dorsal root ganglion neurons express several types of sodium channels that are either sensitive or resistant to tetrodotoxin.
Central Sensitization
This is a form of activity-dependent synaptic plasticity that also has a pivotal role in the pathophysiology of neuropathic pain. It is responsible for secondary hyperalgesia characterized as increased pain intensity to noxious stimuli experienced beyond the distribution of the inciting area of injury, and tactile allodynia , defined as pain due to a normally innocuous stimulus. Central sensitization represents amplification in the functional status of neurons and nociceptive circuits, caused by reduced inhibition, increased membrane excitability, and enhanced synaptic efficacy. Because these changes appear in the central nervous system (CNS) neurons, the perceived pain does not reflect the presence, intensity, or duration of peripheral stimuli. On the contrary, it corresponds to a pathologic state of responsiveness or increased activity of the nociceptive system.
The development of central sensitization often requires high-intensity, repetitive, and continuous noxious input. Induction and maintenance of central sensitization is dependent on N -methyl- d -aspartate receptors (NMDARs) that are ubiquitous within the superficial laminae synapses of the dorsal horn. Normally, the voltage-dependent NMDAR pore is blocked by a magnesium ion (Mg 2+ ). Continuous release of glutamate, substance P, and calcitonin gene–related peptide (CGRP) leads to sufficient membrane depolarization to force Mg 2+ to leave the NMDAR channel , allowing glutamate to bind to the receptor and generate an inward current . This allows entry of calcium ion (Ca 2+ ) into the neuron, activating various intracellular pathways that contribute to the maintenance of central sensitization. This early, acute phase of central sensitization results in activation of intracellular kinases that phosphorylate NMDA subunits and other receptors, enhancing their activity and density and leading to postsynaptic hyperexcitability . Alterations in transcription in the dorsal horn contribute to the delayed or late phase of central sensitization. Increased synthesis of transmitters and neuromodulators, such as glutamate, substance P, CGRP, brain-derived neurotrophic factor (BDNF), or nitric oxide (NO), results in presynaptic functional changes in the dorsal horn. All of these processes can increase membrane excitability, facilitate synaptic strength, and decrease inhibitory influences on dorsal horn neurons. Of note, these alterations are not necessarily restricted to the activated synapse ( homosynaptic facilitation ) but can easily spread to adjacent synapses ( hetero-synaptic facilitation ). Consequently, these modulatory processes lead to enhanced responsiveness of nociceptive neurons , which lasts longer than the initiating stimuli, or results in activation of nociceptive networks by stimuli that are subthreshold compared with the preinjury baseline.
Disinhibition
Several local inhibitory circuits and descending inhibitory pathways serve to modulate the perception of pain. However, after peripheral nerve injury, primary afferents, dorsal horn neurons, and gamma-aminobutyric acid (GABA)ergic inhibitory neurons undergo a number of maladaptive changes. Primary afferents express fewer opioid receptors, and dorsal horn neurons are less susceptible to inhibition by mu opioid agonists. Activation of GABAergic receptors may provoke paradoxic excitation and spontaneous activity. This loss of local inhibition promotes pain transmission, especially the Aβ-fiber–mediated pain.
Low-Threshold aβ-Fiber–mediated Pain
These fibers mediate not only touch, pressure, vibratory, and joint movement sensation but also, and very importantly, the suppression of nociceptive pain caused by rubbing the affected area. However, after neural lesions, Aβ fibers begin to activate superficial dorsal horn nociceptive projection neurons. Peripheral injury induces regenerative responses to help damaged neurons in reconnecting with their targets. These gene-activated growth stimuli may cause sprouting of Aβ fibers into the superficial layers of dorsal horn. Regenerative sprouts may demonstrate ectopic activity or be activated by otherwise subthreshold stimuli. Along with central sensitization, these changes manifest clinically as the ability to generate pain in areas outside of injured nerve territories , and is usually coupled with a loss of C-fiber terminals.
Neuroimmune Interactions
Macrophages have a central role in the immune surveillance of the peripheral nervous system. They clear cellular debris and serve as antigen-presenting cells to activate T lymphocytes. Both macrophages and T cells use cytokines and chemokines as means of communication with neurons, oligodendrocytes, Schwann cells, and spinal microglia. Peripheral nerve injury unleashes microglial activation in the dorsal horn; this occurs in close proximity to the injured afferent. The activated spinal microglia express chemokine receptors and release immune mediators (interleukin [IL]-1B, IL-6, tumor necrosis factor-alpha [TNF-alpha], BDNF), inducing and maintaining maladaptive pain conditions. Mediators released by microglia and astrocytes, as well as cytokines/chemokines produced by DRG cells directly activate nociceptors, cause peripheral sensitization by increasing the excitability of primary afferents, and stimulate adjacent chemokine-expressing neurons. Changes in the expression and function of the transient receptor potential channels and increases in sodium and calcium currents contribute to induction of action potentials. TNF-alpha also has been shown to stimulate DRG neurons and enhance the expression of chemokines, and its antagonists abolish neuropathic pain behavior in animal models.
Thalamic Pain Syndrome
Thalamic pain syndrome (TPS) , first described by Déjerine and Roussy in 1906, is a central neuropathic pain disorder primarily resulting from a thalamic infarct or hemorrhage referred to as central poststroke pain (CPSP) . Other nonthalamic central nervous system lesions occasionally have similar symptoms, broadening the central pain syndrome perspective . The defining clinical features include an initial contralateral feeling of numbness or tingling with compromised tactile sensation, sometimes with hemiparesis if the adjacent internal capsule is affected. Subsequently, as these symptoms gradually dissipate, a persistent, extremely uncomfortable allodynia develops, that is, hypersensitivity to stimuli that normally do not cause pain, particularly to the least degree of mechanical or thermal stimuli. CPSP usually develops within a few months or, rarely, years later after the inciting stroke, occurring in a small percentage of stroke patients, particularly so in senior citizens. There is a broad spectrum of severity; an annoying numbness to a debilitating condition, severely impacting quality of life while undercutting rehabilitation efforts. The patient is often unable to sit still only a short time, may wear a glove to avoid touching anything, often pleading—almost crying out—for help, and eventually experiences psychologic disturbances, bringing the previously self-sufficient, stalwart patient to tears, with eventual concern for potential suicide risk. Treatment options are typically ineffective; the pain severity varies from an annoyance to almost overwhelming, something most individuals have never previously experienced.
Pain Characteristics
The patient typically reports a burning, stinging, stabbing, or shooting pain; hyperalgesia to temperature and touch are often noted. Pain may travel unilaterally from the extremities to sometimes being accompanied by facial paresthesias; anesthesia may also occur in regions affected by the stroke. CPSP is more common in right-sided strokes. Primarily, this is a very persistent syndrome with daily intermittent pain lasting seconds to minutes. The occasional relief is limited to a few hours; however; the hypersensitivity, hyperpathia, or allodynia continue in response to various stimuli.
Pathophysiology
The thalamus plays a central role in modulation of sensory information between the periphery and cerebral cortex. There are various hypothesized mechanisms underlying the pathophysiology of CPSP, including central imbalance, central disinhibition, and central sensitization. Central imbalance is associated with the clinical finding of dissociated sensory loss characterized by hypersensitivity to thermal and noxious stimuli, with preserved sensory perception to touch and vibration. It is speculated that this symptom pattern is attributable to an imbalance of inputs among spinothalamic tracts and spared dorsal column/medial lemniscus activity. Central disinhibition may account for abnormal thermal sensation with burning pain and cold allodynia related to the medial thalamus and anterior cingulate cortex. The concept of central sensitization postulates that changes in electrophysiologic properties of nociceptive neurons lead to hyperexcitability through multiple mechanisms. There is still no acceptable precise clinical correlation with a specific underlying pathophysiologic mechanism.
Treatment
Management of CPSP remains a major therapeutic challenge due to the severity and quality of the pain, the associated unilateral spasticity, and psychologic distress. Each area must be addressed. There are few class I randomized controlled therapeutic (RCT) trials. Lately, new pharmacologic treatments are emerging. One randomized controlled study of pregabalin demonstrated significant reduction in pain intensity as well as improvements in sleep and global patient status. There is evidence for the dose-dependent analgesic benefit of opioids in these syndromes. A recent duloxetine study demonstrated that despite some advantageous biologic effects, this is no more effective in controlling neuropathic pain than placebo.
Currently, a multistep pharmacologic approach is endorsed by some experts specializing in CPSP treatment; however, no trials are yet published, supporting a polypharmacy algorithm. Some pain physicians advocate tricyclic antidepressants and gabapentin as first-line treatment. If improvement in pain intensity is not seen and the pain has a shooting characteristic, then anticonvulsants, such as carbamazepine, are added to the medication regimen. The timing of incorporation of opioids must be tailored to individual patient risk factors for drug-dependent behavior.
Invasive procedures include deep brain, spinal cord, motor cortex stimulation, and various ablative approaches are reported in small series with modest and, unfortunately, often short-lived therapeutic benefit. Patients with CPSP sometimes also benefit from psychologic treatment addressing chronic pain behaviors, and the poststroke rehabilitation seems to be of utmost importance in this group of patients.
Complex Regional Pain
Complex regional pain syndrome (CRPS), previously known as reflex sympathetic dystrophy, is an important chronic neuropathic pain syndrome with a distinctive clinical phenomenology. The epidemiology of CRPS is difficult to estimate due to the spectrum of symptom severity and frequent paucity of clinical signs. Studies maximizing diagnostic sensitivity suggest a postsurgical incidence as high as 30% and 20% to 25% in extremity fractures; chronic “severe” CRPS occurs in less than 2% of these patients. The ratio of CRPS occurrence in women versus men is 2 : 1 to 3 : 1, and more frequently affects the arm in adults and leg in children.
Pathophysiology
This is enigmatic; one CRPS theory suggests that cutaneous innervation is altered post-traumatically. Human pathologic studies demonstrate reduced local nociceptive fiber density with aberrant hair follicles and sweat glands innervation. However, it is not clear whether this is the primary pathology or a reaction to the painful symptoms.
Other studies propose that some central and peripheral sensitization leads to CRPS. Hyperalgesia and allodynia encountered after initial tissue trauma are attributed to local release of pronociceptive neuropeptides, leading to enhanced nociceptor responsiveness with lowered thresholds for innocuous thermal and mechanical stimuli. Higher preoperative pain intensity may predict postoperative CRPS invoking a central sensitization theory. Neuropeptides and proinflammatory cytokines released from injured nociceptive fibers are implicated in experimental neurogenic inflammation. Neuropeptides, such as calcitonin gene–related peptide (CGRP), substance P, and bradykinin, cause vasodilation, increase vessel permeability, hyperhidrosis, and hair growth in the affected area, leading to characteristic CRPS features.
Sympathetic nervous system dysfunction (SNSD) may account for common autonomic CRPS features. Reduced SNS-induced vasoconstriction predicts CRPS and explains the warm, red extremity in acute CRPS. Concomitantly, SNSD may contribute to post-traumatic nociceptive excitation through adrenergic receptors expressed on nociceptive fibers.
In addition, the central nervous system (CNS) may have a CRPS pathophysiologic role. The region of somatosensory cortex representing the affected limb is considerably reduced. Such brain plasticity is associated with greater pain intensity, hyperalgesia, and impaired tactile discrimination. Motor dysfunction accompanying CRPS may be linked to significant reorganization of central motor circuits.
Clinical Features and Diagnosis
CRPS occurs predominantly with fractures and various surgeries, including total knee replacement, hip arthroplasty, carpal tunnel release, and numerous arthroscopic procedures. Major clinical CRPS features include spontaneous pain, allodynia, hyperalgesia, edema, vasomotor instability, autonomic dysfunction, and progressive trophic changes. CRPS pain occurs in a distribution beyond an initially affected nerve(s); eventually, this may involve the entire affected limb, and rarely, the contralateral limb. Weakness and tremor may occur, leading to profound functional loss. CRPS occurs as two subtypes: type I CRPS has no identifiable focal nerve lesion, often developing after minor fracture or trauma, whereas type II CRPS has specific nerve damage.
CRPS is diagnosed by clinical evaluation; there are no specific widely recognized diagnostic tests. Various diagnostic tools have their advocates, but the diagnosis remains clinical. Sympathetic nerve blocks at various levels of the neuraxis are sometimes used to support the presence of an autonomic component. If successful (>50% reduction in pain intensity), a more durable blockade with phenol or a radiofrequency ablation procedure may be performed.
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