Abstract
Background : Clinicians and researchers who pursue challenges in the complexities of neuropathic pain should have a foundation of knowledge in the neuroscience of central sensitization (CS). CS pain represents the augmentation of a broad spectrum of noxious sensory experiences in a pathologic excitatory feedback loop. Design : Drawing on the intricate biology that has evolved from investigations into this phenomenon over the last century, an imbalance in bidirectional pain excitatory and inhibitory pathways has been illustrated in the pain transmission and recognition system. This chapter expands our view of how the central nervous system interacts with peripheral-central nociceptors, the neuroimmune system, and the social, genetic, and the psychological influences that add context to the human experience of chronic pain. Principal findings : Central sensitization syndromes reflect multiple processes that go awry in the encoding of our sensory physical-biological and psychosocial emotional environment. Assessment schemes using validated tools may be applied to initiate and stimulate a platform for additional study. Currently available singular medical and nonmedical management paradigms provide limited utility in modulating these individual conditions. Conclusions : Multimodal approaches using the sphere of current and emerging neurobehavioral and innovative medical interventions are encouraged by this knowledge. Closing this widely distributed pathologic loop by better understanding the mechanisms involved and working to balance the facilitators and inhibitory elements of CS is an essential driving element for all pain clinicians.
Keywords
Central sensitization, Chronic fatigue-fibromyalgia syndrome, Chronic pain, Hyperalgesia, Musculoskeletal pain, Neuroendocrine system, Neuroimmunomodulation
Background and Demographics of Chronic Pain and Central Sensitization
In the 2010 Web-based survey of 35,718 US adults, 30.7% of responders identified themselves to meet criteria for chronic pain defined as “chronic, recurrent, or long-lasting pain lasting for at least 3–6 months.” That a near third of our adult population identifies themselves as afflicted with this sensory experience should not be a surprise. Pain is an interpretation of collective signals from our central nervous system monitoring systems that there are measured consequences to physical or emotional real or perceived threats. Central sensitization (CS) is a key concept to comprehend in developing an essential foundation of knowledge of how sensory communication can misfire and lead to chronic pain encompassing a host of central sensitization syndromes (CSSs) that are discussed in this chapter ( Fig. 2.1 ). Identification of a physically altering or damaging life event as chronic pain implies a real or anticipated threat to homeostasis (maintenance of a constant internal environment) or allostasis (neuroendocrine adaption to stress). Pain and suffering are an experiential reality of our cognitive-emotional species. In an imperfect world where humankind is assaulted with an uneven or seemingly unfair advantage and disadvantage, it is no wonder that 30% of US adults relate their life experience as being in a state of chronic pain, physical, psychological, or metaphysical, with a heightened state of perceived threat.
Those 70% of us with a baseline absent awareness of somatic pain symptoms have a privileged vantage point. Neuropathic pain (NP) symptoms in particular present a heuristic challenge to track down the generator or source of what appears to be a referred symptom or cluster of symptoms. Clinicians are frequently consulted by individuals with very different daily reference points of wellness, obscured by chronic pain, and they offer them only temporizing treatments. Connecting the somatic signals or semiotics of the sensory experience within the realm of chronic neuropathic pain (CNP) requires a working knowledge of how the central nervous system (CNS) processes and defuses or amplifies mechanical, thermal, or chemically mediated peripheral stimuli to be interpreted as central CNP. This chapter aims to provide a working scheme for clinicians seeking to interpret and modulate the signs and symptoms of chronic pain that has become centralized then sensitized or found to be primarily generated and perpetuated within the CNS itself.
What Is Central Sensitization?
CS of pain as described by Woolf in a seminal article in 2011 refers to an amplification of neural signaling within the CNS eliciting pain hypersensitivity. An enhanced pain response to noxious stimulus occurs in somatosensory pathways attributed to bidirectional (i.e., afferent or efferent) increases in synaptic efficacy and reductions in inhibition. Amplification of the nociceptive signal is attributed to an augmented amplitude, duration, and spatial extension of pain in the somatosensory cortex. Temporal summation, a repetitive, consistent level of noxious stimulus to peripheral C-fibers, has been shown to create a progressive increase in the perceived intensity of the stimulus. A decreased sensory threshold required for pain perception is produced. Additional strengthening of normally ineffective synapses recruits subliminal inputs such that inputs in low threshold sensory inputs can now activate the pain circuit. The two parallel sensory pathways, i.e., strengthened stimuli and low thresholds, converge to augment pain perception. Terms frequently referred to in this chapter are summarized briefly in Box 2.1 .
Central Sensitization
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Increase responsiveness (amplification) of nociceptive neurons in the central nervous system to normal or subthreshold afferent input
Peripheral Sensitization
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Increase responsiveness and reduce threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields
Neuropathic Pain
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Pain caused by a lesion or disease of the somatosensory nervous system
Central Sensitization Syndromes
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Syndromes with features of amplification of nociceptive or neuroendocrine-immune stress
Nociception
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Neural process of encoding noxious stimuli
Windup
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Repeated stimulation of C-fibers increasing the intensity of pain
Kindling
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Causation model whereby small stimuli induce an enhanced pain response
Why Is Central Sensitization an Important Topic to Pain Clinicians?
Irrespective of the source, pain remains a subjective end point of a host of sensory, electrochemical impulses, physical and emotional, pathologically perceived aspects of the human environment. The qualia or sensory experience of one individual may be starkly different from that of another person, which speaks to the very fabric of what makes humans unique. Sensory associations are collected and interpreted throughout our lives. Sensitization is a reflection of multiple processes that go awry in the process of encoding the sensory experiences of our physical and emotional environment. A better understanding of the factors that contribute to the sensation of pain allows pain clinicians to untangle this web and address what is correctable or develop adaptations to what cannot be “fixed.”
Pain Syndromes Associated With Central Sensitization
Disease states that amplify pain associated with CSS are often those conditions that defy imaging or straightforward laboratory analysis. Fibromyalgia syndrome (FMS) and complex regional pain syndrome (CRPS) are common conditions seen in our pain clinics. Additional medical diagnoses associated with the CSS ( Fig. 2.1 ) include chronic mechanical low back pain, chronic whiplash-associated disorders, temporomandibular joint disorders, myofascial pain syndrome, pelvic pain disorders, osteoarthritis and rheumatoid arthritis, chronic fatigue syndrome (CF), chronic headache, and irritable bowel syndrome. Symptoms associated with these conditions may include hypersensitivity to bright light, touch, noise, chemical pesticides and herbicides, mechanical pressure, and extremes of temperature and intolerance to multiple medications. Additional symptoms ( Fig. 2.2 ) associated with CS may be difficult to differentiate from other commonly seen chronic pain settings, which include unrefreshed sleep, concentration difficulties, a sense of swelling in the limbs, tingling, and numbness.
Peripheral to Central Sensitization
Organisms require a pain defense mechanism to survive. The early warning system of our human peripheral nervous system (PNS) comprises specialized mechanical, thermal, and/or chemical peripheral receptors or nociceptors. These nociceptors are unusually simplistic and respond uniquely only to mechanical, thermal, or chemical established threshold stimuli to initiate transduction or the process of electrochemical transformation of a noxious signal into a transmissible neural signal. The transduced signal is then transmitted by high-threshold primary sensory neurons. During inflammation, cutaneous and deeper mechanosensitized nociceptors in joints and muscle are recruited from a resting, silent state to barrage the dorsal horn of the spinal cord. Wide dynamic range neurons first described by Mendell in 1966 identified in the dorsal horn receive peripheral nociceptive signals from mechanical, thermal, and chemical activity within a broad range of intensities. Interneurons within the gray matter of the spinal cord relay afferent signals and then perpetuate a nociceptive action potential in the ascending tracts of the cord. Ectopic discharges from inflamed and impaired nerve fibers may occur in rhythmic to intermittent bursts along the low-threshold Aβ- and higher threshold A∂- and C-fibers. Additional theory holds that the contiguous uninjured nerve fibers may be responsible for nociceptive transmission. For example, damage to the L5 nerve root was found to propagate spontaneous action potentials in C fibers of the unaffected L4 dorsal root.
Clinical Manifestations of Central Sensitization
On a clinical level, CS manifested by myofascial trigger points has been demonstrated to represent histologic changes that differ from normal muscle tissue. Using microanalytic methods and equipment, Shah et al. have measured by lower pH levels, increased levels of substance P (SP), calcitonin gene-related peptide, tumor necrosis factor (TNF) α, and interleukin 1β in muscles with active and/or latent trigger points. Each of these inflammatory histochemical markers has a role in increasing pain and sensitivity and has been identified as elevated in or near myofascial trigger points. Sensitized muscle nociceptors have lower thresholds to weak and/or innocuous stimuli and are hallmarks of CS-related muscle pain symptoms. Latremoliere and Woolf have extensively illustrated that neuroplastic changes in the properties of neurons and neural transduction and transmission best represent the underpinnings of CS. Complex CNS mechanisms are daunting to explain or demonstrate. With this collected research, CS has become a scientific challenge to the medical community to explore, better characterize, understand, explain, and develop equally sophisticated systems of assessment and management. All told, peripheral sensitivity is a veritable soup of chemosensitizing mediators and pop-up expressed receptors navigating through channels by various means. The end game is transduction of noxious mechanical, thermal, or chemical stimuli. This is manifested clinically by the sensitization or amplification of nociception at available specialized peripheral neural terminals. What clinicians detect may be the trigger points of myofascial pain or tender points of fibromyalgia. What imaging and standard electrophysiologic testing detect at this point is not perceptible or practically reproducible at this time.
Anatomy of Central Sensitization in the Brain: The Pain Neuromatrix
To paraphrase Moseley, “pain detectors are the eyes of the brain, one mechanism by which the body is protected.” Extending that logic to a view of persistent pain, sensitization represents the “amplitude knob” of these sensors becoming out of control in chronic pain. Touch or mechanoreception is the only primary sensory experience that cannot be turned on or off. Taste, smell, sight, and hearing can be voluntarily suppressed or completely averted. The capacity of being aware of oneself physically (kinesthesia) is attributed to the neuromatrix of mesolimbic structures and the somatosensory cortex that provide feedback as to spatial awareness, magnitude and localization of touch, pressure, and painful threats to existence. Differentiating pleasant from painful touch is meaning or context related; thus, cognitive and complex mechanoreception is transmitted through similar Aδ- and C-fiber pathways to the dorsal root ganglion and then through to the spinothalamic-cortical system. The pain neuromatrix of the brain’s neural network receives an aberrant neurosignature described by Melzack as a “continuous out-flow from the body-self neuromatrix.” The neurosignature forms after cyclic CNS processing and creates the synthesis of a characteristic “signature” on what Melzack terms the “neural sentient hub.”
Four major cortical areas of the brain are felt to be responsible for the neurosignature of pain. The area identified as the primary pain neuromatrix is inclusive of the somatosensory cortex (SI), secondary somatosensory cortex (SII), the anterior insula cortex, and the anterior cingulate cortex (ACC). Registration of pain or threat of pain requires interoception or the capacity of the brain to incorporate the self-perceptive subjective physical and emotional sense of the physiologic condition of the individual.
Contrasting views of the neuromatrix have been disseminated. Canavero finds the pain matrix to be a multimodal network related to the detection of and reaction to salient sensory inputs regardless of a nociceptive pathway but more likely to involve nonnociceptive cognitive processes. Apkarian likewise states that there is no unitary set of brain areas imaged precisely, especially for chronic pain conditions. Physical versus social pain may differ in selective brain imaging studies. Anticipation of pain lights up affective areas of the prefrontal cortex and motor areas of the cerebellum. Ghosts of the CP neurosignature stem from a systemic failure to protect the homeostasis of the person perceiving the tissue damage or threat of injury. Changes in the way these structures connect or communicate (connectomies) within the neuromatrix are more likely to be at fault in CP.
Regional areas of the brain involved in sensory, affective, and cognitive aspects of pain have been demonstrated by functional magnetic resonance imagery (fMRI). Increased fMRI activity in patients with identified acute pain sensation and emotional representations overlap in the forebrain area. This includes the ACC in the prefrontal cortex and insula. The overactive pain neural matrix in CSS enhances brain activity in these regions not involved in acute pain sensations, including the brainstem, the dorsolateral frontal cortex, and the parietal associated cortex. The brainstem may specifically play a role in the maintenance of CS. Long-term potentiation (LTP) is a key neuroplastic capacity of the CNS that facilitates chemical synapses to change their strength. LTP is one of the essential elements in the neural mechanism of memory and learning initially derived from neuroscience experiments by Lomo in 1966. Long-term potentiation of synapses in the ACC, nucleus accumbens, insula, and sensorimotor cortex embeds this disproportionate nociceptive neuromatrix response.
Neuroendocrine Immune System Function in Central Sensitization Syndromes
CSSs, with limited objective markers, have long been burdened with an onus of proving their legitimacy. These conditions are often considered among syndromes labeled with the terminology of medically unexplained symptoms. Common to each of these constellations of conditions, such as FMS, CF, CRPS, and IBS, is the theme of “stress-related illness.” Tremendous strides have been made since the 1970s in the understanding of the role of the hypothalamic-pituitary-adrenal axis (HPAA) in the perpetuation and formation of stress-related disease conditions. CSSs are now better recognized but are still defined primarily by clinical diagnosis. CSS-related brain pathology may now be objectively demonstrated by fMRI and MR spectroscopy as other well-recognized and studied neuroendocrine immune–related conditions.
Communication between the immune system and the brain is mediated by proinflammatory cytokines, including TNF, interleukin-1 (IL-1), and IL-6. These cytokines are responsible for the early immune response to stressful challenge by attracting and activating immune cells. Blocking the action of these cytokines can prevent the generation of sickness responses normally elicited by peripheral immune challenges. Proinflammatory cytokines within the CNS are instrumental in creating sickness responses. These responses include fever, myalgias, arthralgias, neuralgias, decreased activity, and changes in sleep, along with decreased social and sexual behavior.
Glial cells (or microglia) in the spinal cord or astrocytes are the predominant sources of cytokines. Blockade of their actions in the CNS prevents simulated sickness responses, and cytokines introduced to the CNS induce expression of sickness. Proteins from cytokines have two key sites of action, at the site of peripheral immune challenge and within the CNS sites that create this sickness sequela. Microglia express proinflammatory cytokines that exert indirect effects on neuronal nociception, including potentiating N -methyl- d -aspartic acid (NMDA) channel openings and glutamate transport. When sufficient amounts of SP and glutamate are released in the dorsal horn, Mg 2+ is detached or unplugged from the NMDA channels, allowing Ca 2+ to flow into these ion-gated channels activating nitric oxide and prostaglandins. An exaggerated release of these transmitters results in the amplification of nociceptive messages relayed to higher brain thalamic and the brain’s pain neuromatrix areas.
Opioids and Glial Activity
Exposure to chronic opioids for the management of pain has paradoxically been demonstrated to stimulate glial activation and thus thwart pain control. Opioid treatment failure is mediated through a class of pattern recognition immune receptors termed toll-like receptors (TLRs). Enantiomers of various opioid analgesics (morphine, fentanyl, methadone) as well as their metabolites (morphine3-glucoronide) act as agonists to TLR4, promoting a constant low-level release of cytokines, chronic fatigue-fibromyalgia syndrome and IL-1 β. Consequent loss of opioid efficacy, tolerance, dependence, and potential allodynia and hyperalgesia are thus promulgated. Antagonists to TLRs and attenuation of glial activity suppress pain and present a promising pharmacologic target for nonopioid treatment of NP. The role of TLRs is felt to be pivotal to perpetuating NP. Glial-modulating drugs (methotrexate, low-dose naltrexone) may calm the activated glia, causing them to revert to their quiescent resting state.
Biopsychosocial Aspects of Central Sensitization Syndromes
It is critical to the management of any chronic pain disorder that practitioners take into account where and in whom the pain exists. The meaning of pain to each individual patient is embodied in the environment in which that individual lives and functions. The capacity to interpret CS symptoms as a threat or perceived threat is an instinctive, emotional, and cognitive function filtered through a fine mesh of memories and learned behaviors. Whether the noxious stimuli lead to habituation or sensitization is determined by multiple neural exchanges and relays, in part biology and in part psychology, and finally is culturally or socially influenced ( Fig. 2.3 ).
