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13 Articles in Volume 18, Issue #6
Authorities’ Use of Big Data May Harm—or Help—Your Chances of Investigation
Gaps in the Pharmacist’s Pain Management Role
How can cyproheptadine manage complicated chronic pain cases?
Letters to the Editor: Trackable Pills; Buprenorphine; CRPS Diagnosis
Managing a New High-Dose Opioid Patient
Managing Opioid Use Disorder
Medication Selection for Comorbid Pain Management (Part 2)
Mobile Trackers and Digital Therapeutics
New Insights in Understanding Chronic, Central Pain
Nocebo Effects: How to Prevent them in Patients
Polarizing Topics in Chronic Pain
The Fight to End Peripheral Neuropathy
Urine Drug Monitoring

New Insights in Understanding Chronic, Central Pain

A review of recent research advances—coupled with case illustrations—offers a guide for better recognizing non-cancer-related centralized pain.

During the past few years, there have been significant breakthroughs in the medical community’s understanding of chronic, non-cancer-related central pain. In addition to reviewing the updated terminology and classification of central pain, this paper examines recent studies that have elucidated the mechanisms involved in central pain, initially using fibromyalgia as the prototypic illness. The role of central pain in a variety of other chronic painful conditions, as well as in systemic, rheumatic diseases, are also explored using case illustrations.

Updated Terminology and Classification

Chronic pain has been traditionally defined as lasting more than 3 months or lasting beyond that expected following normal healing. It affects hundreds of millions of people, estimated at one-third of the world’s population at any single time. Until about the year 2000, “chronic pain” was attributed to an ongoing peripheral noxious stimulus, usually classified as inflammatory, neurogenic, or structural in nature. “Central pain” was a term used to describe idiopathic, chronic pain following a brain injury.

Research by Clifford Woolf and colleagues demonstrated that chronic pain may be explained by aberrant central nervous system pain processing, hence the term “central” or “centralized” pain.1 Today, central pain is characterized by hyperalgesia, an increased response to a noxious stimulus, and allodynia, a painful response to a stimulus considered to be non-noxious. This categorization has been broadened to include any chronic pain not conforming to peripheral, nociceptive pathways and is considered one of four chronic pain categories, which also include inflammatory, structural, and neurogenic (see Figure 1).

However, it has become increasingly clear that subdividing chronic pain into these four categories may be misleading since central pain is an important contributor to inflammatory, structural, and neurogenic pain. Pain categories are fluid and may change over time in a single individual, as described in the patient examples herein.

In an attempt to develop an evidence-based taxonomy for chronic pain disorders, the Analgesic, Anesthetic, and Addiction Clinical Trials Translations Innovations Opportunities and Networks (ACTTION) redefined chronic pain conditions in 2014 according to their proposed biopsychological mechanisms: peripheral, musculoskeletal, orofacial, visceral, and unclassified (see Table I).2 The initial organization of these chronic pain categories known as the ACTTION-American Pain Society Pain Taxonomy (AAPT) has provided a framework for various pain specialists to come to a consensus regarding chronic pain classifications.

“Central pain,” also called “central sensitivity” or “centralized pain,” is therefore the term now used to encompass any condition wherein pain is generated from the central, rather than the peripheral, nervous system. This type of pain may be the primary source of pain, as in the classic central pain disorders, fibromyalgia syndrome, irritable bowel syndrome, tension-type chronic headaches, temporomandibular joint syndrome, and chronic pelvic/bladder pain syndromes.

Central pain is also considered to be dysfunctional, which to some clinicians implies psychogenic. The clinical phenotype includes generalized pain, fatigue, sleep and mood disturbances. Central pain may also be associated with depression, catastrophizing, and other psychological states but is not considered a psychiatric illness.

Fibromyalgia: A Prototype for Central Pain Patient Example

A 48-year-old female complains of generalized musculoskeletal (MSK) pain on a daily basis for more than 5 years. The pain has not been associated with any joint swelling or inflammation and she describes that, “It feels as if I always have the flu.” She also has persistent fatigue and does not sleep well, often awaking in pain. She never feels refreshed in the morning. Her past medical history includes long-standing tension-type headaches and a bout of depression shortly after delivering her first child 15 years ago. Currently, she reports no mood disturbances although admits feeling increasingly frustrated about her lack of well being.

On examination there is no obvious joint swelling or inflammation and no sign of joint deformities. The general neurologic evaluation is unremarkable. She is quite tender with modest pressure around soft tissue areas including over the neck, shoulders, outer hips, and the chest wall. There were no other physical abnormalities. Laboratory studies included a normal complete blood count, a normal chemistry profile, normal thyroid function tests, and a normal erythrocyte sedimentation rate (ESR).

This patient meets the criteria for fibromyalgia.3 She has more than five years of widespread MSK pain associated with fatigue and sleep disturbance. There is no evidence of joint inflammation or an underlying systemic arthritis or a systemic connective tissue disease. Basic laboratory tests, including ESR, are unremarkable.

Review & Discussion

Fibromyalgia is the most common form of unexplained widespread MSK pain, affecting 2 to 6% of the global population. Chronic widespread pain not related to a specific structural disease, is even more common, affecting 5 to 15% of the population. There is no clear boundary separating chronic widespread pain from fibromyalgia.

Thus, fibromyalgia offers a clear clinical prototype for central pain and has been the model condition in research attempting to elucidate the pathophysiologic mechanisms of centralized pain for decades.3,4 Although there is no single, reproducible polymorphism or haplotype associated with fibromyalgia, a number of studies have found modest genetic influences.

The odds ratio of developing fibromyalgia is 8-fold greater in a relative of a person with fibromyalgia than a relative of a person with rheumatoid arthritis.5 Polymorphisms in genes associated with pain sensitivity, including catechol-O-methyltransferase (COMT), the serotonin transporter gene (5-HTTLPR), adrenergic-receptor genes and mu-opioid genes, have been noted in fibromyalgia, although the strongest evidence has been from genome-wide linkage data.6 Interactions of mu-opioid receptor and serotonergic genes were found to modify pain sensitivity in fibromyalgia patients.7

There is no known cause of fibromyalgia although various physical and emotional stressors may be precipitating factors. Mood and sleep disturbances and chronic fatigue are present in the vast majority of patients. This triad of symptoms should be considered part of the phenotype of central pain. Certain personality traits, particularly catastrophizing, have been important risk factors in fibromyalgia and related central pain disorders as well, as shown in Table II.4-7 Various physical and emotional stressors have been noted to be precipitating factors in fibromyalgia, raising the possibility of altered hypothalamic pituitary-adrenal axis function.1,3,4 Physical trauma, such as repetitive strain, obesity, and chronic inflammatory and immune disorders, such as rheumatoid arthritis, predispose to fibromyalgia and central pain.

Fibromyalgia patients have been found to have a heightened sensitivity to heat and mechanical pressure as well as prolonged temporal pain summation.8 Functional, structural and chemical neuroimaging studies have provided the strongest evidence for central pain in fibromyalgia (see Table III). Regional blood flow variability, changes in insular glutamine levels, and structural loss of grey matter, for example, have been noted in fibromyalgia patients compared to pain-free controls.9-11 In addition, decreased mu opioid receptor availability has been found in fibromyalgia subjects.12 The structural and functional changes of the disease, including decreased regional coherence, decreased cortical thickness, and decreased brain volume, overlap and correlate with the severity and duration of chronic pain.13

Neuroimaging advances looking at the extent that brain regions are connected to each other (functional connectivity) has proven particularly useful in identifying central pain mechanisms in fibromyalgia. Resting state functional connectivity examines the intrinsic neural transmission between brain regions. Fibromyalgia patients have demonstrated increased connectivity in parts of the brain important in pain transmission, such as the posterior insula, and with neural regions not associated with pain, such as the default mode network.14,15

A functional MRI-based neurologic signature was proposed for fibromyalgia patients composed of augmented responses in sensory integration in the insula and medial prefrontal regions and reduced responses in the lateral frontal cortex (see Figure 2).16

Fibromyalgia patients with the highest levels of glutamate in the posterior insula were those most likely to respond to pregabalin and their subsequent pain improvement correlated with significant normalization of functional MRI and connectivity findings.17 Fibromyalgia patients treated with milnacipran have also demonstrated increased pain inhibitory response on MRI.18

IBS and Chronic Pelvic/Bladder Pain Patient Example

A 35-year-old female has a history of gastrointestinal irritability, including alternating constipation and diarrhea, with bloating, abdominal pain and food intolerance, since she was a teenager. At age 29, she began noting recurrent bladder irritability and intermittent pelvic pain. She was diagnosed with interstitial cystitis by a urologist and treated with installation of various substances into the bladder without significant improvement. One year later, she began complaining of increasing pelvic pain that was exacerbated by intercourse. A general pelvic examination was unremarkable. During the past year, she has been exhausted and not sleeping well. She reports never feeling refreshed when she awakens in the morning. She also complains of neck and shoulder pain associated with frequent headaches and generalized muscle soreness. She feels sad but has not been diagnosed with depression. Her physical examination demonstrates no significant abnormalities.

The patient’s symptoms are consistent with irritable bowel syndrome (IBS) as well as chronic pelvic/bladder pain. She also describes symptoms consistent with fibromyalgia and chronic muscular headaches. As noted above, her symptoms of chronic pain, fatigue, sleep and mood disturbances fit the clinical picture of a central pain disorder.

Review & Discussion

Indeed, IBS, chronic pelvic/bladder pain, chronic headaches, temporomandibular joint syndrome, and chronic fatigue syndrome share phenotypic and pathophysiologic features with fibromyalgia and should be classified as chronic central pain disorders. The odds ratio for comorbidity of fibromyalgia, chronic headaches, IBS, temporomandibular joint syndrome, and chronic bladder and pelvic pain has varied from 3 to 20 in twin studies and in large population surveys.19

As with this patient, a vast majority of patients with chronic pelvic or bladder pain complain of pain in other sites and their widespread pain score correlates with depression, sleep disturbance, and worse quality of life.20 Generalized allodynia has been noted by various experimental techniques in patients with IBS, migraine and tension-type headaches, and chronic pelvic/bladder pain.21-23 Patients with IBS and chronic pelvic pain have also demonstrated altered neural connectivity and abnormal response to experimental pain in the insula and anterior cingulate.24,25 Structural brain changes were found in IBS subjects compared to controls.26 This included lower brain volumes in the bilateral superior frontal gyrus, the bilateral insula and bilateral amygdala and the brainstem.

MRIs of women with chronic pelvic/bladder pain syndrome have demonstrated numerous white matter abnormalities that correlated with pain severity, urinary symptoms, and impaired quality of life.27 Regional white matter abnormalities distinguished patients with urological chronic pelvic pain syndromes from subjects with IBS and from healthy controls as well.28

Chronic, Widespread Rheumatic Pain Patient Example

A 58-year-old female has a 25-year history of rheumatoid arthritis (RA) that was initially treated with nonsteroidal anti-inflammatory drugs and methotrexate. However, because of persistent pain and swelling, she was placed on etanercept approximately 10 years ago. On that medication, she had an excellent clinical response and her rheumatologist told her that she was in remission. The methotrexate was discontinued three years ago and she is now taking etanercept intermittently and has had no exacerbation of joint swelling or inflammation.

However, over the past 18 months, she reports having generalized muscle and joint soreness and achiness as well as persistent exhaustion and sleep disturbances. She describes these symptoms as being similar to when she first developed RA but has not noted any recurrent joint swelling. Physical examination reveals finger joint deformities but no joint swelling or redness and minimal joint tenderness. Patient is very tender in multiple soft tissue locations over the neck, outer elbows, outer hips, and chest wall. Laboratory studies include a normal complete blood count (CBC), normal ESR, normal C-reactive protein test (CRP) with positive rheumatoid factor, unchanged from prior evaluations.

With a history of RA, this patient has been in clinical remission since a biologic medication was added to her original treatment with methotrexate. For one-and-a-half half years, she has experienced widespread pain and fatigue as well as sleep disturbances. The examination reveals multiple areas of tenderness, all consistent with fibromyalgia. The absence of any joint swelling as well as the normal ESR and CRP indicate that the RA continues to be in remission.

Review & Discussion

Fibromyalgia or chronic, widespread pain is more common in individuals with RA, as well as in each of the systemic connective tissue diseases, compared to the general population.29 The prevalence of fibromyalgia has varied from 15 to 40% in patients with rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, and ankylosing spondylitis.29 Evidence of central sensitization has been even more evident in each of the rheumatic diseases, including osteoarthritis.

The presence of centralized pain accounts for elevated scores on rheumatic disease assessment scales that do not correlate with inflammatory parameters.30 In one study, the presence of concurrent fibromyalgia inversely correlated with CRP and ultrasound evidence of joint inflammation but positively correlated with pain and fatigue severity ratings.30 Concomitant fibromyalgia has led to inappropriate therapy with biologic agents in RA and other systemic rheumatic diseases.31

Patients with RA tend to demonstrate generalized allodynia as well as structural and functional changes consistent with central pain sensitivity.32 Structural changes have included smaller intracranial volume and regional difference in gray matter. In a recent report, 54 patients with RA underwent brain imaging with special attention to the brain connectivity of various neural regions.33 Researches found a correlation of fibromyalgia symptom severity with the functional connectivity of the default mode network to the insula, a characteristic finding in imaging of patients with fibromyalgia (see Figure 3).

Chronic Low Back Pain Patient Example

A 45-year-old male presents with a 5-year history of chronic low back pain which has been getting worse. He was employed in a physically demanding job and has been unable to work for the past two years. He also describes tension-type headaches. He has become increasingly depressed and frustrated. Previous imaging studies demonstrated moderate disc space narrowing and degenerative changes in the lumbar spine. He has been treated with short-acting opioids with minimal improvement.

On physical examination, he walks slowly with an antalgic gait. There is no evidence of any joint swelling or inflammation but he is tender in numerous areas throughout the cervical and lumbar spine. There are no focal neurologic abnormalities.

This patient has chronic low back pain but no significant neuropathic findings or focal imaging abnormalities. It is likely that his pain is primarily central rather than peripheral in nature. Rather than apply an interventional approach such as injections or surgery, it would be appropriate to begin with a multidisciplinary chronic pain management program.

Review & Discussion

One-third of subjects with chronic low back pain also report symptoms consistent with fibromyalgia,34 and more than 40% of patients at a tertiary care spine clinic met the criteria for fibromyalgia.35 The presence of fibromyalgia has been correlated with younger age, greater rate of unemployment/receiving compensation and greater pain, mood disturbances, and worse quality of life. The presence of chronic, widespread pain has also correlated with increased opioid use and poor outcome in subjects’ joint replacement.36

Generalized hyperalgesia, similar to that noted in the fibromyalgia case herein, was present in patients with chronic low back pain.37 Patients with low back pain and fibromyalgia had similar increased pain following pressure, compared to controls, and similar neural activation in pain-related brain regions on MRI.37 Structural and functional neuroimaging abnormalities similar to those reported in fibromyalgia have been found in patients with chronic low back pain; this has included gray matter volume atrophy.37 Brain connectivity changes correlated with a clinical transition of subacute to chronic low back pain.38 Similar to those found in fibromyalgia, altered functional connectivity involving the insula, medial frontal cortex and the default mode network were present in subjects with chronic low back pain.39


There is an emerging body of research that a biologic profile is common to all central pain conditions. This includes heightened pain response to noxious stimuli and chemical, structural, and functional neuroimaging abnormalities. Although a biologic marker is not yet practical, investigators have proposed a neurologic signature for central pain conditions, such as fibromyalgia. It is likely that future research will clarify the central nervous system mechanisms and provide a better therapeutic approach to managing chronic central pain.

The cases presented herein illustrate the spectrum of central pain, with fibromyalgia being the prototype. Chronic pelvic/bladder and irritable bowel syndromes, often felt to have peripheral organ dysfunction, are now also considered to be driven by central pain sensitivity. Centralized pain may complicate any systemic rheumatic diseases and adversely impact outcome. Regional pain disorders, such as chronic low back pain, are often primarily related to central pain as well. Clinicians, therefore, must consider central pain mechanisms whenever evaluating patients with the vast array of chronic pain conditions, from fibromyalgia and IBS to rheumatic or structural diseases. Furthermore, it is crucial to remember that the impact of central pain on structural, inflammatory, or neurogenic pain disorders is not static and may change substantially over time.

Last updated on: October 5, 2018
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Classic Central Pain Syndromes: Review of Neurologic Causes of Pain
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