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11 Articles in Volume 13, Issue #2
Spinal Cord Stimulation: Fundamentals
Assessment of Psychological Screeners for Spinal Cord Stimulation Success
Educating Patients About Pain Medications
Central Sensitization: Common Etiology In Somatoform Disorders
Demystifying Pain Pathways
Vibroacoustic Harp Therapy in Pain Management
Erythrocyte Sedimentation Rate and C-Reactive Protein: Old But Useful Biomarkers for Pain Treatment
Editor's Memo: Inflammatory Disease—Time to Refine Our Diagnoses
Ask the Expert: Pain Persists in Spite of High-dose Opioids
Ask the Expert: Rectally Administered Morphine
Letters to the Editor: Mistaken Hormone, Lab Values

Central Sensitization: Common Etiology In Somatoform Disorders

Central sensitization occurs when pain pathways in the spinal cord become hyperexcitable and are augmented, rather than blocked, in the thalamus and other brain centers. This leads to a cascade of neuroinflammatory, neuroendocrine, and autonomic dysregulation.
Editor's Note: The understanding of centralization of pain from a peripheral pain site is a major scientific discovery of recent times that enhances clinical understanding and therapeutics. Once peripheral pain has centralized, aggressive therapy is required because two anatomical systems, rather than one, must be treated. One of the mysteries of pain patients is what appears to be the "de novo" occurrence in the central nervous system (CNS) of some painful conditions, such as fibromyalgia (FM), interstitial cystitis, temporomandibular joint (TMJ) disorder, and irritable bowel syndrome (IBS). While neuroinflammation resulting from glial cell activation clearly is an underlying mechanism for centralization of peripheral pain, the underlying cause of these disorders is unclear. In a scholarly presentation, the authors attempt to categorize these disorders into one group called "somatoform," purporting that "central sensitization" is a common thread among these disorders. This paper is published here to explore their theory and terminology. The authors do not discuss what produces central sensitization, such as neuroinflammation, autoimmunity, or possible infection. They focus on a hyperirritable nervous system of unknown etiology. There is no endorsement by Practical Pain Management regarding the authors' theories, conclusions, terminology, or treatment. We do endorse the fact that the authors are attempting to better understand these disorders, and, hopefully, this paper will initiate some needed interest and debate.

"Physical symptoms that are unexplained by organic cause are a relatively common phenomenon. It is estimated that modern diagnostic testing can find no organic explanation for 10% of reported and persisting physical symptoms. Furthermore, the occurrence of multiple somatic symptoms is associated with higher rates of psychopathology and predicts poorer treatment outcomes and higher healthcare utilization. Such nonorganic symptom complaints have traditionally been grouped into separate syndromes, such as FM, chronic fatigue, IBS, and TMJ disorders. Historically, different terms have been used to group these types of somatization disorders, including "functional syndromes," "medically unexplained symptoms," and "bodily distress syndrome." These syndromes also share many common features, including pain, fatigue, poor sleep, cognitive deficits, headaches, anxiety, and depression, suggesting that they may share a common etiology."
—Mayer et al.1

Most clinicians have encountered the chronic pain patient who has no specific organic basis for their pain. Among these are patients with chronic fatigue, FM, TMJ disorder, chronic headache, IBS, irritable bladder, and regional pain syndromes (such as non-cardiac chest pain). Typically, such patients have endured frustrating rounds of visits to specialists (cardiologists, rheumatologists, gastroenterologists, and others) and many diagnostic tests, procedures, and treatments—all to no avail. Such encounters are not without their own hazards and may aggravate the patient's fear of undiagnosed illness, a phenomenon called "iatrogenic reinforcement." Over the past decade or so, research has begun to elucidate basic physiological mechanisms for these disorders—namely, central sensitization (CS).2-4

CS involves an abnormal and significant amplification of pain sensations by CNS mechanisms. There is impairment of the nervous system's natural pain suppressive mechanisms (eg, endogenous opioids). Sensations not normally painful become so and minor discomforts become severe (allodynia). Rich interconnections between pain and autonomic pathways lead to visceral organ dysfunction, such as what occurs in IBS.

Yunus has proposed that the term central sensitivity syndrome (CSS) be used for nonorganic somatoform disorders that share this CS etiology.3-5 As will be discussed in this review, the CSS model provides a very appealing theoretical construct that can be used to categorize a wide array of related syndromes. Unlike in the past, when various symptom presentations were viewed as individual somatoform disorders, the CSS model is a unifying one, in which these various symptom presentations are conceptualized as simply many forms of a common CSS construct, with CS as the fundamental root cause.5-8

How Does CS Occur?

How CS comes about is not yet entirely clear. Many patients who develop CS have a history of early childhood—even prenatal—trauma; an abusive, alcoholic, or absent parent; and/or a conflicted, unhappy home life. A family history of CS is common, implying genetic influences (epigenetic regulators, which "turn genes on or off" and respond to environmental influences, may be equally important). Such environmental impacts may induce vulnerability to later stressful life influences. Many patients do well in school and into adult life. However, often one or more setbacks occur at home or at work, or an accident, injury, or even a minor illness can precipitate the disorder, and the frustrating search for cause and cure begins.

CSS: An Overview

Many technological advances have been made for investigating pain disorders,9 and concomitant studies have been conducted that have increased our ability to identify biomarkers of CS.10-14 These contributions have enhanced our understanding of the pathogenesis of pain disorders. For example, we have learned that disorders such as TMJ, FM, and IBS stem from dysregulation of interdependent bodily systems, any one of which can be disturbed from its normal function by multiple causes, and subsequently can impair the function of the next system in a cascade of maladaptive biopsychosocial sequelae.15-18 As such, the biopsychosocial model (first introduced by Engel19) has been demonstrated to be compatible with the nature and complexities of pain pathology. Furthermore, it removes the illusion of simplicity that is assumed by purely physiological models, which are only appropriate for studying etiologies of the "early" phases of pain processing.20 "Early" processing is used to describe the reactivity that occurs prior to the higher-order neurocognitive interpretations of pain that modify the pain signal during the "late" phase of pain processing, producing the perception of pain, and the subjective experience of pain.

Pain Pathways

A primary mechanism of CSS is hypersensitivity.8,18,21,22 One of the complexities of studying and treating chronic pain has been identifying where in the pain pathway the processing is augmented. The difficulty of such a task relates to the fact that responses to pain are variable during the "early" processing of pain in the periphery, and are substantially more variable in the later phases of pain processing, when many factors converge to promote CS and modulate pain processing.

There are many pathways that can lead to altered processing in the late phase that can cause CS. TMJ, for example, has been described as stemming from alterations in either ascending or descending processes along these pathways.23 Ascending processes involved in CS usually are the result of injury or psychophysical causes in which the nociceptive neurons are modified and the pain signal becomes sensitized. Descending processes involved in CS usually are the result of modifications to supraspinal input.24 In response to pain, our body has "built-in" regulatory systems that serve as a defense against the factors involved in positive-feedback circuitry, which would otherwise cause progressive disruption of bodily function through dysregulation.25,26 "Top-down" modulation of pain is one such example of a defense achieved by descending inhibitory pain signals (Figure 1) from the periaqueductal gray (PAG) in the brainstem to the dorsal horn.27 Moreover, pain blocks proper functioning of catecholamines arising from the locus ceruleus, which project to the PAG and then to the dorsal horn in the spine, diminishing the descending inhibitory effect on nociception.28 Poor catecholamine function also can result from emotional distress, such as depression, and is characterized by a down-regulation of α-2 adrenergic receptors along the descending pathway.24,29,30 The result is enhanced α-1 adrenergic processing of norepinephrine along this pathway.

Dysregulation of adrenergic function along the descending pathway is one of the causes of disinhibition and consequential hypersensitivity.29 When processing along the descending pathway is disrupted, the threshold in the sensory neurons in the dorsal horn is lowered, and this induces secondary sensitization in the dorsal horn. Moreover, this form of CS can lead to generalized or widespread pain symptoms and somatic complaints. Furthermore, it explains the more advanced levels of CS, during which it becomes common for comorbid clinical conditions (such as FM and TMJ, among other disorders of the CSS) to occur.1,18,31

The clinical presentation of CS can also be manifested in a number of ways (Table 1).7,8,21 All of these symptoms and their respective mechanisms represent varying levels of CS. For example, neuroplastic changes in the brain and spine can eliminate, or greatly reduce, supraspinal modulation of pain, which can lead to widespread pain and pain that is experienced in the absence of any external stimuli.32 When certain neurochemical or morphological changes occur in the large-diameter A-fibers, normal touch sensation can become interpreted as painful.33,34 Furthermore, the physiological properties of pain operate within complex networks involving interrelated peripheral and central processes. For example, inflammation can cause neurons within the spinal cord and brain to become hyperactive, and hyperactivity can bring about molecular changes in nociceptive neurons leading to an amplified pain signal.35,36 Additionally, latent C-fibers can become activated at lower thresholds, inducing hypersensitivity to noxious stimuli. Each of these levels of CS possesses a unique set of challenges for the systematic study of pain pathology.

Although there is still much to learn regarding the precise processes involved in CS, the transition from adaptive pain responding to "pathologic" states of CSS has been demonstrated and replicated in laboratory settings by observing the transition from primary to secondary hyperalgesia.37-42 However, there still remains a lack of prospective studies of disorders such as TMJ that evaluate some of the more complex symptoms at the more advanced levels of CS. This is largely due to the fact that CSS is characterized by dysregulation in multiple organ systems, including the neuroendocrine, neuroimmunologic, and neurocognitive systems, as well as many neurochemical changes that occur along the pain pathways during the initial stages of CS.43-46 Moreover, the dysregulation influences both the induction and maintenance of CS and the resultant pathology.

Role of Stress

Many of those with CSS are chronically stressed prior to the onset of their pain and symptoms (see sample cases on page 50). In these cases, chronic stress creates a climate for the development of the illness and promotes CS.15-18 The theory of allostasis provides an explanation for these disorders that is strongly associated with hypocortisolism and dysregulation of the sympathetic nervous system, as well as serotonergic, opioid, and immunological functions.25,45 Prolonged pain and chronic stress demand much of the body's energies, leaving little compensation for restoration, which leads to maladaptive functioning. Many of the changes that occur are a consequence of cumulative "wearing down" of important physiological factors that support autonomic pain processing.47

The importance of understanding the influence of stress on augmented pain processing also is validated by the fact that the autonomic nervous system is innervated elegantly throughout the pain pathway. The receptiveness of the autonomic nervous system to physical and psychosocial stressors supports the homeostatic qualities of the pain system.48-50 With all of its facets, pain can be understood as an active, sometimes progressive, sequence of events caused by interrelated peripheral and central factors, including the patient's responsiveness to psychosocial influence and adaptiveness to experience as well as molecular events to which they have been exposed and their genetic predisposition.51,52

The Process of Nociception

There are many types of afferent receptors. A-α and A-β fibers are large-diameter touch neurons responsible for registering proprioception and the "normal touch" sensation.33 A-δ fibers are medium-diameter nociceptive neurons that transmit noxious mechanical, thermal, and chemical stimuli. C-fibers are unmyelinated, small nociceptors that are responsive to nociceptive input. When a stimulus evokes a signal that falls outside of a "normal range," the signal exceeds the threshold and the nociceptors are activated.

Multiple System Dysregulation

Using TMJ as an example, researchers found that TMJ patients were hypersensitive to different types of experimental pain beyond the orofacial region (ie, painful pressure, mechanical cutaneous, and thermal stimuli).53 Additionally, there were observable disruptions along autonomically mediated pain inhibitory pathways.54 Specifically, this study observed differences among "arterial blood pressure, heart rate, heart rate variability, and indirect measures of baroreflex sensitivity." These investigators found that TMJ patients had a distinctly different pattern of autonomic responding, relative to controls. Such findings are consistent with other research suggesting that autonomic dysregulation is a fundamental aspect of TMJ.25,55-57

Augmentation of the hypothalamic-pituitary-adrenal (HPA) axis perhaps is one of the most important underpinnings within a TMJ population and among those with CSS.4,6,18,58 Its primary function is the release of cortisol in response to physical or psychosocial stressors.59 Cortisol acts on bodily systems and regulates the sympathetic nervous system (SNS) in a negative feedback loop. Hypocortisolism occurs when the HPA axis becomes "exhausted" and does not produce enough cortisol to regulate the SNS, which leads to increased vagal tone and subsequent dysregulation of the SNS. Dysregulation of the HPA axis and the SNS neuroendocrine systems leads to increases in norepinephrine in the CNS and periphery.25,55-57 Increases of adrenergic neuropeptide Y, which is an indicator of neuronal norepinephrine output, are also observed. Likewise, the imbalance of these systems leads to dysregulation of immunologic function and increases in pro-inflammatory cytokines—such as interleukin (IL)-1β, IL-6, cyclo-oxygenase, nitrous oxide (NO), nuclear factor κB, tumor necrosis factor-α,and, most importantly, substance P (SP)—which act as nociceptive transmitters.60,61 SP is protective at low levels, but when it is elevated in response to chronic stress, trauma (physical or psychosocial), or pathological states that cause dysregulation of the HPA axis and SNS, neuroinflammation can occur.35,36 It can also cause neuroinflammation along the spinothalamic pain pathway, leading to increases in physical symptoms of CSS.45

Cellular Mechanisms of CS

The basic notion of CS is that the features of the CNS change in ways that amplify and distort pain so that it no longer solely reflects the activity of the peripheral nervous system. One crucial distinction between primary hyperalgesia (or peripheral sensitization) and secondary hyperalgesia (or CS) is the long-term potentiation (LTP) process. This is a process characterized by increased sensitivity in the postsynaptic neurons that involves dependent facilitation in which one set of neurons potentiates the efficacy of a different set of neurons.62 Peripheral sensitization is dependent on homosynaptic facilitation. Moreover, one of the hallmark qualities of CS is an expansion of the sensory afferents' receptive fields. These symptoms translate on many physiological levels, beginning with increases in membrane excitability, increases in the efficacy of postsynaptic neurons through LTP, morphological changes in the expression of receptors, and decreases in inhibitory input.62

In response to repetitive or prolonged stimulation of C-fibers, many (sub) cellular processes occur that can bring about CS. Phosphorylated extracellular signal-regulated kinase (ERK) is activated in response to stimulus intensity and, when activated, sets off a cascade of kinases within the mitogen-activated kinase second-messenger family.10 Kinases can cause morphological changes in neurons by directly and indirectly influencing the distribution of ion channels.63-65 Their influence also is seen in the kinases' ability to modulate membrane excitability. ERK has been compared to c-fos for its validity as a biomarker of neuronal activation and CS after pain. ERK has been demonstrated to exhibit a more immediate response (within one minute) to nociceptive input than c-fos, and to be more closely involved in the events leading to CS along the spinothalamocortical tract, rather than merely an indicator of neuronal activity.10 In fact, inhibitors of ERK such as mitogen-activated protein kinase inhibitors U0126 or PD98059 reduce behavioral measures of CS.10,12 Moreover, ERK has been identified as contributing to the expression of subcellular structures, such as nuclei and cytoplasm, as well as to the morphological changes observed in the axons and dendrites.10

How to Measure CS

Mayer and colleagues developed the Central Sensitization Inventory (CSI; Table 2) as a means of measuring CS.1 In developing the CSI, the authors conducted 2 separate studies. Study 1 revealed the strong psychometric properties of the CSI in a cohort of normal subjects (test-retest reliability of 0.817; Cronbach's alpha of 0.879). In addition, a factor analysis of the CSI (using both normal subjects and patients with chronic pain) yielded 4 major factors that were all related to somatic and emotional symptoms:

  • Physical symptoms
  • Emotional distress
  • Headache/jaw symptoms
  • Urological symptoms

In Study 2, the CSI was administered to 4 different groups: patients with FM; patients with widespread pain (but without FM); patients with work-related regional chronic low back pain; and normal subjects. Analyses of these data revealed that the patients with FM reported the highest CSI scores, whereas the normal subjects reported the lowest scores. In addition, it was found that the prevalence of previously diagnosed CSSs and related disorders was highest in the FM group and lowest in the normal subjects. Finally, in an ongoing study, patients who scored 40 or above on the CSI were independently diagnosed as having a CSS.

These findings demonstrated that the CSI may be a useful tool, in both general and specialty medical clinics, to help identify patients whose presenting medical syndromes may be comorbid symptoms of CSS. Such early identification can then be used to help clinicians develop an appropriate treatment plan. Moreover, a better understanding of the etiological underpinnings of CSS will hopefully lead to more theory-driven clinical research to develop even more effective pharmacological advances for their treatment.

Treatment

Treatment for CSS relies on a multidisciplinary approach. Recovery is based on better stress management skills and techniques that stimulate the body's own natural pain suppression mechanisms, with minimal or no reliance on medications, especially opioids. Some medications that can be helpful are low-dose tricyclic antidepressants, such as nortriptyline; acetaminophen; non-steroidal anti-inflammatory drugs; and gabapentin. Duloxetine (Cymbalta) can be useful to relieve early symptoms. Clonazepam is safe and effective at providing relaxed sleep when taken at bedtime, but can be habit forming with prolonged regular use. However, medical management is not nearly as important as activities that stimulate pain suppression. Exercise—beginning with stretching and proceeding gradually to walking, jogging, cycling, swimming, or some combination for these—is vital, both to suppress pain and to reverse or prevent deconditioning. Yoga and Tai Chi also can help. Showers, first hot then cold, provide good temporary relief, as does gentle massage. Pain management centers provide effective formal structural programs, particularly for resistant patients and those on opioids. A knowledgeable primary care physician and staff are essential to monitor treatment, provide support, and prevent excessive testing and unhelpful treatments. CS patients get sick like anyone else and need help interpreting symptoms accurately.

Summary

With the increase in neuroscience and pain research in recent years, we are beginning to develop a better understanding of biopsychosocial underpinnings of many disorders.9 This has been the case for recent advances that improve understanding of the CSS process and shed light on how it may be a common etiology of an array of somatoform disorders, such as TMJ, IBS, FM, etc. Indeed, a primary symptom of CS is hypersensitivity of pain pathways, and there may be dysregulation of biopsychosocial homeostasis in these patients. There has been encouraging research addressing these issues, which should continue to grow in the future. The significant clinical implications of such research will be that patients with CSS will no longer be viewed as suffering from some "nebulous" form of psychogenic pain that is assumed to be "all in the patient's head." Rather, the best treatment for these patients will require comprehensive interdisciplinary intervention programs that have been shown to be both therapeutic and cost effective.66

Clinical Case Samples of CS/Somatoform Disorders

A Woman With Neck Pain
A 36-year-old married mother of two daughters, ages 5 and 7, comes self-referred with a chief complaint of excruciating neck pain lasting 8 months. Additional symptoms include episodes of pressure in the chest associated with shortness of breath and tingling of the hands; aching in her shoulders and arms; frequent, severe headaches; and frequent urination. Past history includes frequent sore throats in childhood and 2 bouts of "mono." She did well in school, and graduated from college with a degree in art history but has had fatigue, pain, and headaches over the years. She was symptom-free when pregnant and when nursing. Family history is positive for multiple sclerosis in her sister. She uses no tobacco, alcohol, or drugs. Both parents are alcoholics. The father was frequently absent, and home life was chaotic and stressful.

Ear, nose, and throat specialists find no anatomical or functional abnormalities on detailed examination. She has also been to a cardiologist, rheumatologist, gastroenterologist, and a neurologist. Tests have included magnetic resonance imaging of the head and neck, computed tomography of the abdomen, upper and lower endoscopies, and multiple lab tests, all of which have been nondiagnostic.

On examination, the patient is intelligent, well groomed, cooperative, and in no distress. Vital signs are all normal. Positive findings consist of tenderness to palpation beneath the left jaw, spasm in the neck muscles, and tender points about her shoulder girdle, more on the left than on the right. After discussion, she agreed to enter a formal pain management program.

Comment: An example of a primarily regional pain syndrome, with additional overlapping CS manifestations.

A Woman With Chronic Fatigue
A 50-year-old married mother of three presented with a 2-year history of exhaustion, weakness, and easy fatigability. She also reported intermittent constipation and diarrhea with bloating. She gave a history of having had frequent illnesses growing up. She missed 1 year of school due to rheumatic fever. She finished college and married happily. She had few illnesses or complaints until the present illness began. On further questioning, she revealed that there were major problems and conflicts with an extremely angry and rebellious teenage daughter, and no help from her kind but passive husband. She was not on any regular medications. On exam, she appeared well. Positive findings were minimal and limited to minor abdominal tenderness on palpation and some bloating. She was treated with low-dose amitriptyline, a tricyclic antidepressant, and regular supportive reassurance. She ultimately made a complete recovery but only after the daughter's behavior improved.

Comment: This is an example of chronic fatigue and IBS precipitated by domestic stress and potentially conditioned by a childhood pattern of illness (possibly a learned behavior). Not all chronic fatigue syndrome patients, however, have a history of childhood abuse.

A Man With Irritable Bowel
A 75-year-old retired podiatrist is referred from the hypertension clinic for a possible diagnosis of celiac disease. The patient has a history of heavy use of alcohol and tobacco in various forms since his teens. However, he was successful in his career. After a second bout of pancreatitis, he attempted to quit drinking but was unsuccessful. He self-diagnosed celiac disease. The laboratory tests, which are 95% sensitive, were negative, and he declined gastroduodenoscopy and biopsy. He placed himself on a gluten-free diet and achieved relief of his abdominal bloating and cramping.

In terms of other past history, he was a middle sibling. His mother suffered from bouts of depression and binge drinking, and his parents divorced when he was 2 years old. On exam, he was hypertensive but alert, fit, and in no distress. There were no significant positive findings except for mildly elevated blood pressure. His consultants suggested he might have IBS or "non–gluten sensitive celiac disease." The patient again declined duodenal biopsy and continued his chosen lifestyle.

Comment: This is an example of CS in a man with fewer symptoms, frequent recourse to alcohol, and major control issues. Less common in men, the syndrome often is accompanied by antisocial behavior. Non-celiac gluten sensitivity may equate to IBS.

—Mayer et al.1
Last updated on: December 15, 2014
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