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9 Articles in Volume 15, Issue #3
Abuse-Deterrent Formulations
Ask The Expert: False-Positive Screen for Benzodiazepines
Clinical Diagnosis of Centralized Pain in the Age of ICD 10
Editor's Memo: The WHO Pain Treatment 3-Step Ladder
Letters to the Editor: Hormone Dosing, Adhesive Arachnoiditis
Pain in Women
PROMIS Pain-Related Measures: An Overview
Selective Interventional Spinal Techniques: Injections and Ablations
Transcranial Direct Current Stimulation (tDCS): What Pain Practitioners Need to Know

Clinical Diagnosis of Centralized Pain in the Age of ICD 10

Recommendations for a protocol for making a clinical diagnosis of centralized pain.

This Consensus Task Force highly recommends that every chronic pain patient in every clinical setting be evaluated for pain centralization. The historical hallmarks of centralization are constant pain, sleep interference, and fatigue. The presence of pain centralization should be noted in a patient’s record and its clinical ramifications and prognosis communicated to all concerned parties.

Pain centralization is a pathologic state initiated by microglial overactivation, neuro-inflammation, metabolic disturbances, cellular destruction, and neuronal sensitization. It may severely impair patients and require specific treatment measures, so every chronic pain patient in every clinical setting should be evaluated for its presence.

This report provides a protocol to expeditiously make a clinical diagnosis of centralized pain using a rapid history and physical examination. Since centralization produces a large number of clinical manifestations, it is appropriate to label it central pain syndrome or chronic pain syndrome, which have International Classification of Diseases (ICD) 9 and ICD 10 code numbers.

Evolution of Pain

It has long been known that direct insult to the central nervous system (CNS)—trauma, infection, cerebral vascular accident, or disease, such as multiple sclerosis or Parkinson’s disease—can result in persistent pain.1 Pain that results from a direct brain insult has been called central pain for at least 5 decades.

Two relatively recent discoveries have expanded our understanding of pain that affects the CNS.2 One is that some disease processes, such as fibromyalgia, interstitial cystitis, and vulvodynia, are known to involve the CNS.3-5 The other is that a peripheral nerve injury or disease, such as phantom limb pain or some neuromas, can permanently implant pain sensation in the CNS.6-8

Regardless of how the CNS becomes involved with pain, it may become pathologically disturbed.9 The underlying mechanism is microglial cell overactivation, which produces neuro-inflammation, metabolic disturbances, cellular destruction, and neuronal sensitization (Figure 1).9-19 While centralization is the most common term used to denote this pathologic development, various other terms—neuropathic, persistent, intractable, and central sensitization—have been used to describe this condition.

Although there have been a plethora of basic science and imaging studies, reports, and descriptions of centralization, there is no consensus on how a practitioner should make a clinical diagnosis of centralization.9-19 To date, there is no specific laboratory test, so its presence must be clinically determined by history and physical examination. Consequently, Practical Pain Management convened a consensus task force to draft this report and provide a simple and rapid protocol to clinically diagnose the presence of pain centralization. This protocol can be used easily in any clinical setting, and it is a adjunctive screen that is compatible with the 1 to 10 pain scale.

Public Health Issue

Data and information collected to date are limited, but what data are available suggest that pain centralization is a major public health issue. The exact incidence and prevalence are unknown, but 2 recent epidemiologic studies indicate that a staggering number of Americans have centralized pain. A recent review of data from the 2010 National Health Survey found that about 20 million Americans have constant pain, which is one of the hallmark symptoms of centralized pain.20 Another national survey found that about 10 million people in the United States take opioid medications.21 Although the clinical need for opioids compared to non-opioid analgesics such as anti-inflammatories is unclear, it is likely that the need for regular opioid administration indicates the presence of centralization in many patients.

It is clear that centralized pain causes a high degree of suffering, mental and physical impairment, and an inability to care for oneself.22-29 But much about this condition remains a mystery and it is all too often unrecognized and untreated. A goal in developing this clinical protocol is to provide every practitioner in every clinical setting with the ability to rapidly diagnose the presence of centralized pain (Table 1). Only when practitioners across the nation begin making a clinical diagnosis will there be enough additional clarification and identification of the public health ramifications of centralized pain.

The Centralization Process

The process of centralization begins with an injury or disease that affects either brain tissue or peripheral nerves. In either case, microglial cells are activated in the CNS.30-35 These cells migrate and initiate neuroinflammation and the release of toxic substances, including glutamate, that sensitize neurons36 and cause cellular destruction. As a result, the brain tries to return itself to normal (neuroplasticity); in the process, the sensation of pain becomes implanted in CNS tissues.2,6,8,17 (Figure 2).

Studies show that patients with centralized pain produce serum and spinal fluid biomarkers of neuroinflammation.37-40 Magnetic resonance imaging (MRI) studies show that neuroinflammation is associated with loss of gray and white matter.19,41-43 Microglial overactivation, neuroinflammation, and neuronal sensitivity produce a typical set of signs and symptoms that make it possible to clinically recognize the patient who has centralized their pain.9 Typical symptoms include constant pain, insomnia, fatigue, depression, attention deficits, memory loss, and episodes of hyperalgesia and allodynia.

In addition, the autonomic, sympathetic nervous system becomes dysfunctional and overactive (dysautonomia) and produces the physical signs of hypertension, tachycardia, hyperhidrosis, hyperthermia, hyperreflexia, mydriasis, and vasoconstriction that may manifest as cold extremities and resemble Raynaud’s phenomenon.29 (Figure 3).

The hypothalamic-pituitary-adrenal axis is stimulated and several hormones may rise in the serum, including adrenocorticotropin, cortisol, and pregnenolone.44,45 Neuronal cells become overly sensitized and hyperalgesia may be present (central sensitization).32,36 Allodynia, apparently caused by a loss of inhibition of efferent electrical discharges from the CNS, also occurs.46-48 Skin biopsies may show a loss of small fibers, which apparently relates to this phenomenon.

Multiple studies describe the severe interruption of life and suffering of these patients.22-29 Psychologic and social impairment may be profound and include reclusivity, depression, and mental deficiencies, such as a loss of reading and mathematical abilities.49 Patients may be bedbound or housebound. There may be diminishment of hygiene, nutrition, and social interactions (Table 2).23-29

Necessity of Clinical Diagnosis

There are several reasons that a clinical diagnosis of centralization should be made. First and foremost is that centralized pain mandates a different treatment strategy than peripheral pain. To treat centralized pain, pharmacologic, hormonal, and nutritional agents must cross the blood brain barrier and interact with CNS elements, such as receptors, neurotransmitters, and microglial cells. Centralized pain carries a different prognosis than does purely peripheral pain. In addition, there is no evidence that centralized pain is curable. It is a chronic, indolent inflammatory disorder that is subject to control, reduction in severity, and, possibly, remission, but total elimination has not been demonstrated. Patients, families, pharmacies, regulators, payors, and all other concerned parties must be educated about the fundamental pathology and prognosis of centralized pain. Lastly, the presence and clinical diagnosis of pain centralization must fit into the ICD 9 and ICD 10.

Critieria for Clinical Diagnosis

A clinical diagnosis of centralized pain is, we believe, justified and required if some specific historic and physical findings are present. The clinical diagnosis is presumed because there is no confirmatory laboratory test or x-ray at this time. Supportive laboratory tests, including serum biomarkers of neuroinflammation and abnormal hormone levels, can be done.40,44,45 MRIs that show evidence of tissue destruction or inflammation also are supportive.41-43

The essential necessities or hallmarks of a clinical diagnosis of centralization are: presence of a neurologic disease or injury, pain, insomnia, and fatigue.

A variety of symptoms and behaviors may be produced by centralized pain, including depression, anorexia, reclusivity, and generalized muscle (myofascial) pain. The protocol here lists 15 symptoms, and we suggest that the presence of at least 7 of these symptoms indicates the presence of centralized pain. Some physical signs of excess autonomic sympathetic discharge as well as hyperalgesia (excess pain on pressure) and allodynia (pain to light touch) help support the diagnosis. Nine physical signs are listed in the protocol, and we recommend that at least 3 be present for a diagnosis of centralized pain (Table 2). It is the intent of this consensus report to give the practitioner a rapid method to diagnose centralized pain. Once centralization is determined to be present, the panel recommends a more detailed evaluation of the patient; however, the specifics of this evaluation are beyond the scope of this report.

Concomitant Presence Of Peripheral Pain

Many patients will have a painful peripheral site as well as centralization. We believe that any peripheral pain site should be given a specific diagnosis separate from centralization. Not only may central and peripheral pain sites coexist, they both must be treated. Some studies indicate that a peripheral painful condition may maintain centralization, and aggressive treatment of a peripheral pain site, such as lumbar spine or hip, or peripheral neuropathy pain may lessen the severity of centralization.50,51

Terminology and the ICD Classifications

The term, central pain has been used for years to refer to pain caused by direct brain injury or disease process.1 Now that we know that a non-direct injury or disease can centralize, the term central may optionally be expanded. To highlight the problem of neuronal sensitivity, hyperalgesia, allodynia, and excess sympathetic discharge, the term central sensitization has been popular and has been used to indicate that centralization has occurred.33,36 The term neuropathic literally means pathologic nerve, but in recent years it has been used to indicate that either central or peripheral pain has continued past the time of normal healing and has been associated with symptoms of burning, electricity, and “pins and needles.”29 Many literary and scientific articles now use neuropathic pain as an alternative term for centralization.12,29 Other terms such as persistent, spontaneous, or intractable commonly are used.

Although we have no quarrel with the emergence of new clinical terms, we have identified a problem in that the terms neuropathic, central sensitization, intractable, spontaneous, and persistent are not in the ICD 9 and ICD 10. Be advised that the simple term central pain is labeled central pain syndrome in ICD 9 and ICD 10.

In this age of electronic medical records, computerized billing, and the high costs of pain care, we recommend that practitioners attempt to match their clinical diagnosis with an ICD classification whenever possible. Table 3 lists the ICD 9 and ICD 10 code numbers for the 5 major classes of pain diagnoses. Practitioners who wish to use terms for centralized pain not found in ICD 9 and ICD 10, such as neuropathic, intractable, thalamic, persistent, spontaneous, or sensitization, should attach the words central or centralized to their preferred term. For example, we suggest central neuropathic or central intractable pain.

The reality is that pharmacies, laboratories, imaging centers, hospitals, clinics, and third-party payors all use electronic and computerized records and require an ICD 9 and ICD 10 diagnosis. ICD 9 and ICD 10 codes may even be necessary on prescriptions and laboratory requests.

Fitting Centralization Into ICD

The current ICD 9 classification and codes were adopted in 1975, and ICD 10 was developed in 1995. The latter is to be implemented in October of this year. Although the major pain classifications were adopted almost 3 decades ago, long before our current understanding of centralization, we believe the ICD classification is compatible with the new scientific information on pain centralization.

There is a specific code in the ICD 9 and ICD 10 classifications for central pain syndrome. Although practitioners arbitrarily may believe that there is a clinical difference between central pain and central pain syndrome, the former is not listed in ICD 9 and ICD 10. We believe that a patient given the clinical diagnosis of centralized pain, regardless of initiating cause, should, now, be labeled central pain syndrome or chronic pain syndrome.

It is interesting that in 1975, the drafters of ICD 9 differentiated between chronic pain and chronic pain syndrome. Although we are not informed as to their reasoning in 1975, we believe that the drafters of ICD 9 must have recognized a complicated pain syndrome that had mental and physical aberrations in addition to simple, chronic pain. The drafters of ICD 9 called this condition chronic pain syndrome, which in all probability, and unknown to the drafters of ICD 9 and ICD 10, was centralized pain.

Some notes and descriptions attached to this label in ICD 10 documents mention that an indication for the diagnosis of chronic pain syndrome includes psychosocial complications. This task force, therefore, believes that chronic pain syndrome (338.4) and central pain syndrome (338.0) are both appropriate labels for centralized pain.(Table 4).


Centralization of pain is a pathologic state that results from microglial activation, neuroinflammation, metabolic disturbances, tissue destruction, and neuronal sensitization. In addition to constant pain, a number of physiologic abnormalities occur, including sleep interference, fatigue, and depression. There is hyper-stimulation of the hypothalamic-pituitary-adrenal axis and the autonomic-sympathetic nervous systems.

As a result of the many pathologic aberrations caused by pain centralization, the patient may be so physiologically and psychologically impaired that they become reclusive, antisocial, and unable to carry out activities of daily living. Due to the many facets of this process, it is clinically appropriate to refer to this state as central pain syndrome or chronic pain syndrome because these 2 labels are listed as such in the ICD. If other terms not listed in the ICD, such as neuropathic, sensitization, intractable, or persistent, are clinically used as labels, it is recommended that the term central or peripheral be attached to indicate if centralization has occurred.

The recognition and treatment of centralized pain probably is the biggest unmet need in pain management. At this time, the incidence and prevalence of centralized pain is not known precisely, but it undoubtedly ranks as one of the biggest public health problems in America. The aging population may increase the prevalence of centralization.

This consensus task force highly recommends that every chronic pain patient in every clinical setting be evaluated for the presence of pain centralization. The historical hallmarks of centralization are constant pain, sleep interference, and fatigue. The presence of pain centralization should be noted in a patient’s record and its clinical ramifications and prognosis communicated to all concerned parties.

Last updated on: May 10, 2017
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Glial Cell Activation and Neuroinflammation: How They Cause Centralized Pain

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