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11 Articles in Volume 10, Issue #9
Activated Glia: Targets for the Treatment of Neuropathic Pain
Acute Herpes Zoster Neuritis and Postherpetic Neuralgia
Acute Treatment of Cluster Headache
Chronic Overuse Sports Injuries in the Adolescent/Pediatric Population
Clinical Recognition of Central Abnormal Neuroplasticity
H-Wave® Stimulation: A Novel Approach In Electromedicine
Homeopathy Enters Contemporary Pain Practice
Immune-modulating Effects of Therapeutic Laser
Pain and Addiction: Words, Meanings, and Actions in the Age of the DSM-5
Partial Plantar Fasciectomy With Autologous Platelet Concentrate
Tethered Spinal Cord Syndrome: Pathophysiology and Radiologic Diagnosis

Clinical Recognition of Central Abnormal Neuroplasticity

Arguably the major scientific research finding in the Decade of Pain is that severe pain causes rearrangement or reconfiguration of nerve cells in the central nervous system.1-8 This rearrangement or transformation, called neuroplasticity, is a response to electronic impulses that arise from a peripheral pain site that is not healed by the body’s basic immune response to a painful injury.1,7

The ramifications of this finding are profound for clinical treatment, disability determination, epidemiologic outcomes, and even terminology. While the term ‘neuroplasticity’ simply means rearrangement or transformation without a positive or negative connotation, the result in this case is negative as it produces an abnormal cellular structure, altered electronic circuitry, and encoding of the memory of the initiating pain. Precisely how this occurs is unclear but it is essentially the mechanism of phantom limb pain.9 It is incumbent on all pain practitioners to understand the development of central abnormal neuroplasticity (CAN) and clinically recognize its probable existence in pain patients.

Presented here is a first time attempt to clinically characterize and profile the patient with CAN so we can begin to identify these unfortunate patients at the clinic level. We must now view patients with this condition as having a central brain disease in addition to a peripheral pain-initiating site. The clinical diagnosis must now be made by an old-fashioned history and physical exam. Although the scientific underpinning of this phenomenon has primarily been documented by sophisticated neuroimaging studies, there is no standard imaging technique yet available for routine clinical use. Consequently, the profile for probable or suspected diagnosis of CAN given here will demand refinement and advances as we learn more about it. The diagnosis of CAN should not replace current nomenclature, but be a secondary diagnosis such as “intractable pain with likely CAN.”

Evidence of Existence

The evidence that central abnormal plasticity develops and encodes the memory of pain is well documented by a large number of research and clinical studies.1-8 The model for understanding this phenomenon is phantom limb pain.9 The patient with severe hip, spine, or other pain condition may develop an encoded memory of pain in nerve cells just like the amputee.4,7,11 It’s just that the patient still has their spine, nerve, joint, hip or other initiating pain site.

Anatomical Abnormalities

The various neuroimaging studies and other clinically-related investigations clearly demonstrate the presence of CAN. Glial cell and neurons are affected as there may be loss of gray and white matter including opioid and dopamine receptors.2,3,6 There appears to be little consistency as to the site of the brain neuroplasticity. Various reports involve the cortex, thalamus, hippocampus, corpus callosum, amygdyla, and cingulate gyrus. The great variance in the brain imaging studies showing loss of tissue is puzzling and a concern to clinicians. Why? If the neuroimaging studies showed a uniform anatomic loss of tissue and neuroplasticity in chronic pain patients, it would make a clinical diagnosis more specific and treatment strategies could be more targeted.

At this time, the neuroimaging studies clearly document the presence of neuroplasticity as indicated by tissue loss, but there appears considerable variability among chronic pain patients. This fact leaves us with a limited ability to make a specific clinical diagnosis. Therefore, I recommend that pain practitioners simply state in their records, for example, that the patient has suspected, probable, or likely CAN.

Severity

At this time, it appears that the pain and disability that CAN may produce can be clinically graded by the medical standard of mild, moderate, or severe. CAN is strictly a clinical diagnosis at this point as there is no laboratory, radiologic, or electric wave assessment that has been correlated with severity. Additionally, the brain imaging studies used to determine neuroplasticity with tissue loss and restructuring are far from being available to routine clinical practice.

Known to all pain practitioners is the tragic severity of pain that is called Reflex Sympathetic Dystrophy or Chronic Regional Pain Syndrome. In some of these cases, CAN appears to cause paralysis or retardation of movement. CAN also appears to be related to reports of twitches, jerks, and restless legs commonly reported by chronic pain patients.

Major Historical Characteristics

A careful history will usually identify the patients with suspected CAN. They will clearly state that their pain is constant (“24/7”) unless asleep. Additionally, sleep will usually require a medical sleep aid. This is in contrast to the patient who describes their pain, for example, as being intermittent, varies in intensity, comes in waves, or exacerbates with certain physical activities.

The patient with constant pain will invariably date their pain to a certain point in time. Often they can identify the date and hour that their pain became constant. In most cases, they relate that they originally had an intermittent pattern of pain that abruptly converted to a constant state. Others relate that the constant pain started at the instant of an accident or surgery. They frequently report that surgery made their pain worse. In reality, the surgery, per se, was probably quite sound but the stressful event precipitated CAN with it’s encoding of the memory of their pain. The severe case will describe great impairment of social, vocational, and familial functions. They report being bed- or house-bound in the absence of medication. In addition, they relate loss of memory and attention span.

Peripheral Pain Site Responds Poorly

A second hallmark characteristic of CAN is that local, peripheral treatments do little, or nothing, for the pain. For example, the usual chronic arthritis patient with intermittent or non-constant pain will report local pain site treatments such as oral anti-inflammatory agents, topical analgesics, injections, electromagnetic measures, and physical therapies to be effective. This may not be the case with CAN because central-encoded pain will require agents that act in the spinal cord and central nervous system to reduce pain. Some patients with CAN will not even experience much pain relief if the peripheral pain site is anesthetized.

The initiating pain site may show little sign of inflammation, inadequate healing, or pain on physical manipulation such as pressure or stretching. The peripheral pain site may have what appears to be rather good healing following surgery or injury. As part of a diagnostic evaluation, the pain practitioner should attempt some peripheral pain treatments to determine if the peripheral pain site is active. This might include a topical analgesic, oral anti-inflammatory agent, or anesthetic injection. If there is little or no response to a peripheral treatment, one may then suspect the presence of CAN.

Major Physical Findings

For reasons that are unclear, patients with CAN often exhibit significant sympathetic discharge. Symptoms and signs of excess sympathetic outflow may include hypertension, tachycardia, vasoconstriction, diaphoresis, hyperreflexia, nausea, mydriasis, piloerection, anxiety and insomnia. This phenomenon may be due to neuroplastic changes and tissue loss that normally inhibit sympathetic outflow. Vasoconstriction is evidenced by cold hands and feet. Raynaud’s phenomenon (e.g., blue and cold hands or feet) is occasionally present.

Hormonal Changes

CAN is highly associated with hypothalamic-pituitary stimulation. It is unclear whether this is merely a stress response or reaction related to CAN’s abnormal neural circuitry. Initially, the pituitary secretes adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), thyroid stimulating hormone (TSH) and follicle stimulating hormone (FSH) into the general circulation as a response to stress and hypothalamic prohormones. Adrenals, thyroid, and gonads respond with serum elevations of their respective hormones. Given enough stimulation over time, the pituitary and end organ glands may reach exhaustion resulting in low serum levels of cortisol, testosterone, thyroid, pregnenolone and possibly others.

Psychiatric Symptoms

Depression, paranoia, lethargy, lack of memory and mental concentration are common symptoms in these patients. Admittedly, these symptoms may be caused by a plethora of other factors including nutrition, culture, stress, and lack of sleep. It is clear, however, that the hormonal changes such as hypercortisolemia associated with CAN may injure receptors in the amygdala that may cause depression.

Response to Medication

Probably due to loss of tissue and various receptors, patients with CAN respond to medications in an unpredictable manner. Treatment regimens for pain control may have to be quite unusual and even “bizarre” in that they will often vary considerably from the norm. Some patients with CAN will report ineffectiveness of some drug classes and some may require high dosages. Interestingly, patients with CAN tend to respond quite well to stimulants and antidepressants and this may be related to the loss of dopamine receptors in CAN.12 Given the great variability of brain tissue loss and cell restructuring among patients with CAN, practitioners will have to experiment with various treatment regimens in each patient to find one that will provide pain relief and control the high level of sympathetic outflow characteristic of the group.

Summary

No other research endeavor stands out in the Decade of Pain more than the discovery that severe pain causes neuroplastic changes in the central nervous system that somehow encode the memory of pain. Just as in phantom limb pain, the peripheral, originating pain site may be healed thus mimicking an absent, amputated extremity.

The researchers who have documented neuroplasticity by neuroimaging and other studies have truly made a profound contribution and are duly recognized here.1-8 Their efforts now allow practitioners to begin using this knowledge at the clinical level. Presented here is one observer’s efforts to profile and characterize patients who have suspected CAN (see Table 1).

Table 1. Signs and Symptoms of Chronic Pain Patients with Presumed Central Abnormal Neuroplasticity

1. History
  a. Pain is constant
  b. Often pain has a sudden onset

2. Poor response to local or peripheral pain treatments such as topical analgesics

3. Excess sympathetic outflow signs
  
Tachycardia    Anxiety Hypertension Insomnia
   Vasoconstriction Nausea Diaphoresis Piloerection

4. Hormone abnormalities such as elevated or depressed serum cortisol, pregnenolone, or ACTH

5. Psychiatric symptoms
   Depression     Memory Loss Paranoia
   Reduced Attention Span         Lethargy

6. Requires a high dose and/or unusual treatment regimen

Note: it is emphasized that CAN is strictly a clinical diagnosis suspected to be present when a number of signs and symptoms in the table are present.

The two hallmarks of a patient with CAN are one whose pain is constant and whose peripheral, originating pain site is either absent or healed and doesn’t respond to local and peripheral treatments such as injections, topical medications, prolotherapy, physical or electromagnetic measures, or anti-inflammatory agents. These patients characteristically exhibit sympathetic outflow signs with symptoms of tachycardia, hypertension, vasoconstriction, diaphoreses, piloerection, nausea, anxiety, and insomnia. Hormonal disturbances are extremely common as indicated by elevated serum cortisol and pregnenolone until such time as pituitary and adrenal exhaustion occurs and serum levels of some pituitary and adrenal hormones drop below normal. Pain control and treatment in these patients is difficult as tissue loss and cell rearrangement may render some medications rather ineffective. Practitioners may have to be creative and experiment to find a good pain control regimen. At this time, there is only symptomatic but no curative treatment. Understanding that some chronic pain patients have CAN rather than a peripheral pain problem should lead investigators to look for, and find, some curative approaches. For now, clinical identification and profiling of suspected CAN is the first step.

Last updated on: November 2, 2016
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