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13 Articles in Volume 11, Issue #7
Fibromyalgia: Practical Approaches To Diagnosis and Treatment
Juvenile Fibromyalgia: Diagnostic Challenges and Treatment Options
Aqua Therapy Helpful in Treatment Of Systemic Lupus Erythematosus
Axial Neck Pain, Radiculopathy, and Myelopathy: Recognition and Treatment
Early Treatment of TMD May Prevent Chronic Pain and Disability
Identifying Psychological Factors That Influence Surgical Outcomes
Managing Morton’s Entrapment
Premedicated Mask May Hold Promise for Migraine Patients
Mother With Low Back Pain
The Hip Replacement Patient
Evidence-based Medicine: Losing the Patient’s Voice?
What Is Going Wrong With Research?
Risk for Sedation and Car Accidents

The Hip Replacement Patient

Pain that transforms from peripheral to central pain can create treatment dilemmas for many pain practitioners. If not rapidly controlled, microglial cells may release excitatory amino acids, such as glutamate, nitric oxide, and proinflammatory cytokines, which damage central nervous system tissue.


A 60-year-old woman underwent hip replacement surgery. The surgeon reported a good technical result, and x-rays showed good placement of the metal implant. After leaving the hospital, the patient experienced constant pain that was so severe she could not maintain her position as an executive in the financial industry. Over the course of the next 2 years, the patient underwent a number of failed pain treatments, including intralesional corticosteroid injections, acupuncture, prolotherapy, physical therapy, electromagnetic measures, nerve blocks, and topical lidocaine patch.

Laboratory findings included the following:

  • Erythrocyte sedimentation rate (ESR), 65 mm per hour (normal is <30 mm/h)
  • C-reactive protein (CRP), 3.20 mg/dL (normal is <0.80 mg/dL)
  • Slightly elevated early morning serum cortisol, 21 mcg/dL (normal is 5-18 mcg/dL)

Physical exam revealed no pain on pressure when applied around the hip joint. The patient had some hyperactive reflexes and cold extremities.

By now, most practitioners are aware of the discovery that peripheral pain may migrate to the central nervous system (CNS) and imprint itself into its memory.1-9 But does this discovery have practical ramifications for clinical practice? The answer is simply yes. Why? Treatments directed at peripheral pain will be ineffective if the pain has transformed itself into a central pain. Additionally, a diagnosis of central pain clearly has practical ramifications for prognosis.

Based on this new knowledge, every patient with chronic pain must be evaluated to determine if the pain is peripheral, central, or a combination of both. This article is a primer on how to recognize central pain transformation so that the pain practitioner can select better treatment options and educate patients about the consequences of this transformation.

How and Why Does Transformation Occur?
Any painful peripheral condition can, unfortunately, transform itself into central pain (Table 1, page 36). The transformation of postsurgical pain into central pain is one of the most studied conditions, as surgery is a traumatic event that damages many nerves. Injured nerves are believed to emit inflammatory stimulators, and possibly some electronic signals, that reach glial cells in the spinal cord and brain.3-9 Microglia, the smallest glial cells, comprise about 5% to 10% of all glial cells (the other 90% to 95% are astrocytes). Once activated by chemical stimuli, microglia change their morphology into amoeboid phagocytes.

The microglia instigate neuroinflammation that, like inflammation elsewhere in the body, is initially neuroprotective. Unfortunately, if the pain is not rapidly cured or controlled, microglial cells may produce too much inflammation.10-12 With excess neuroinflammation, microglial cells release excitatory amino acids, such as glutamate, nitric oxide, and proinflammatory cytokines. This process causes CNS cell death, apoptosis, and tissue atrophy.12 Cells attempt to heal or reform (neuroplasticity), but in this cellular transformation, the perception (also called memory or sensation) of pain is imprinted (also called encoded or embedded) in the cells of the brain.3-9

If the peripheral pain is not cured, it is believed that microglial cells remain activated, neuroinflammation continues, and brain tissue continues to shrink and atrophy. Numerous magnetic resonance imaging (MRI) studies have now demonstrated this loss of brain matter.13-17 When loss of brain tissue occurs, any number of brain functions may be altered, and some very deleterious impairments, such as dementia, may occur.

Predisposing Factors
In surgical patients, postoperative follow-up studies indicate that central pain may occur faster and with greater severity depending on preoperative pain, size of surgical cuts, and lack of pre- and postoperative analgesia.18-20 Any genetic neurologic disease or trait also may predispose to both occurrence and severity of central pain. Included here are depression, bipolar illness, attention-deficit disorder, post-traumatic stress disorder, dementia, addiction, and childhood sexual and physical abuse. When central pain occurs, it may worsen the underlying disease and require treatment of both conditions.21,22

Time Required for Central Transformation
As noted, the time it takes for peripheral pain to transform to central pain can be quite varied. With very traumatic events, such as head and neck injury, it can be almost immediate. Most cases appear to occur about 6 to 12 weeks postinjury. Some patients may have only peripheral pain for several years, but suddenly transformation may take place, perhaps precipitated by a new injury or illness. These patients give a history that their pain was mild, intermittent, and responded to simple measures, such as anti-inflammatory agents and topical treatments, until suddenly the pain became severe, constant, and unresponsive to the old, simple, stand-by measures.

Diagnosis of Central Pain
There are two major historical hallmarks of central pain. The first is that central pain is usually constant. Patients complain that it is present “24/7” and never goes away. Constancy is apparently due to permanent imprinting or encoding of the memory of pain in the brain’s cellular structures.

Peripheral pain, on the other hand, is not constant. It will be present some days or for some time with varying severity, but it is not constant. Peripheral pain ebbs and flows as it is part of an anatomic site that has variations in blood flow, lymph node drainage, and electrical conduction. The patient’s movement, activities, and temperature also influence peripheral pain.

The second hallmark of central pain is that patients respond poorly—or not at all—to treatments aimed at peripheral pain, including injection techniques, topical agents, electromagnetic measures, acupuncture, prolotherapy, and physical therapy. Practitioners should take careful note as to whether a patient responds poorly or not at all to these peripheral treatments. A poor or nonexistent response is a sign that transformation has occurred. On physical examination, the classic findings of swelling, redness, elevated temperature, or pain on pressure or slight movement, is not present. The patient can point to the site of the pain and describe the pain as severe, but applying pressure to that site does not make the pain better or worse.

In the early, developing phase of central pain, neuroinflammation and resulting abnormal cell reformation is believed to abolish a great number of inhibitory descending pathways in the brain and spinal cord.3,5 This may result in unchecked, descending electronic signals that may exhibit as allodynia, hyperalgesia, or burning sensation.

A similar loss of inhibitory control also may occur in the brain, which may result in pituitary overstim-
ulation and excess sympathetic discharge recognized by hypertension, tachycardia, mydriasis, diaphoresis, hyperreflexia, and vasoconstriction exhibited by cold hands and feet. Patients may exhibit elevated ESR and CRP levels, both of which are nonspecific markers of inflammation including neuroinflammation. Pituitary over-
stimulation may cause elevated adrenal and gonadal hormone serum levels including cortisol, pregnenolone, and testosterone. If the overstimulation process goes on too long, the pituitary and adrenal glands may become exhausted, at which time cortisol and other adrenal–gonadal hormones may show low serum levels. Table 2 provides a diagnostic summary chart that includes a check list to help diagnose central pain. Practitioners should attempt to classify each chronic pain patient as to whether he or she has peripheral or central pain, or a combination of both.

Can Central and Peripheral Pain Coexist?
Many patients with central pain respond somewhat to some peripheral treatments because the peripheral site has never totally healed. The fear is that peripheral pain sites will remain active and continue to foster neuroinflammation in the CNS.

A recent study of 18 patients with chronic low back pain examined whether aggressive measures (spine surgery or facet cortisol injections) for low back pain could reverse brain tissue loss. By reviewing functional MRIs, the authors found that
6 months after treatment, patients in the treatment group had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls.23

The authors noted that increased DLPFC thickness correlated with the reduction of both pain and physical disability. In summary, every effort should be made to cure active, peripheral pain to prevent or minimize CNS neuroinflammation and central pain.

The Central Sensitization Disorders
In recent years, some observers have referred to fibromyalgia (FM), irritable bowel syndrome (IBS), and interstitial cystitis as central sensitization disorders. With FM in particular, there are typical, central pain signs and symptoms including constant pain “all over,” insomnia, allodynia, hyperalgesia, pituitary–adrenal hormone abnormalities, and excess sympathetic discharge manifested by such signs as hypertension, tachycardia, and cold extremities.15,17 “Sensitization” refers to glial cell activation and neuroinflammation so that a stimulus like touch or pressure causes exacerbated excess pain (hyperalgesia). One argument about these so-called central sensitization disorders is whether the pain originated in the periphery and transformed into central pain or whether the pain arose in the brain. For example, some investigators believe that most FM pain originates around a bony structure such as the cervical spine.

Other cases, including IBS and interstitial cystitis, may originate in the CNS possibly as a result of exposure to a virus or toxin. Certainly, it is well known that central pain can originate in the CNS as neurologic conditions, including stroke, multiple sclerosis, Parkinson’s disease, and amyotropic lateral sclerosis. These conditions all have neuroinflammation, apoptosis, and reformation as an underlying mechanism.

Many pain treatment regimens now in use consist of opioids, anti-inflammatory agents, antidepressants, stimulants, and neuropathic agents and have, without realization, been more directed at central rather than peripheral pain. They should continue to be used until a better understanding of central pain emerges.

It must be clearly recognized, however, that these agents are all symptomatic, not curative. I believe that our challenge is to regenerate CNS tissue, and that will have to be at least partially done with anabolic hormones that are known to effect CNS cells. Trials are currently under way to test human chorionic gonadotropin progesterone, pregnenolone, and oxytocin.

Among the recent great discoveries in pain science is that peripheral pain may transform into central pain. This phenomenon occurs when damaged nerves emit chemical substances that activate microglial cells in the CNS. Microglial cells initially produce a neuroprotective inflammatory response, but this response may give way to a destructive neuroinflammatory reaction that damages and destroys CNS cells. As damaged cells try to reform, the memory or perception of pain is permanently imprinted or encoded in them. Brain tissue loss and atrophy can be so significant that it can be observed on an MRI.

The historical clinical hallmarks of central pain are that it is constant (ie, “24/7” in the words of patients) and the patient will report little or no response to peripheral treatments such as corticoid injections, surgery, electromagnetic measures, acupuncture, and topical anesthetics. Physical examination may reveal allodynia or hyperalgesia in the early phases of central pain, but when central pain establishes itself, the peripheral pain site will not exhibit the usual findings of swelling, redness, elevated temperature, or pain on pressure. Laboratory findings may show elevated inflammatory markers (ESR, CRP). The pituitary–adrenal–gonadal axis is overstimulated in central pain and may show abnormal cortisol, and other hormone levels. Excess sympathetic discharge is almost universal and manifested by hypertension, tachycardia, mydriasis, diaphoresis, and vasoconstriction with cold hands and feet. Practitioners are urged to immediately begin classifying their chronic pain patients as to whether their pain is central, peripheral, or both.

Last updated on: December 1, 2011
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