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10 Articles in Volume 14, Issue #2
How Safe Is Epidural Steroid Injection? Examining Drug-Related Factors
How Important Is Evidence-Based Medicine in Epidural Injection for Low Back Pain?
Current Access to Opioids—Survey of Chronic Pain Patients
Opioid Prescribing Part 2: Appropriate Documentation of Follow-up Visits
Neuropathic Pain: A Literature Review
Translating Chronic Pain Research Into Practice: Chronic Pain and the Brain
Intractable Pain: Time To Understand and Use the Term (Again)
Are Antibiotics a Treatment Option for Low Back Pain?
Genetic Mutations in Cytrochrome P 450 2D6
Light Exercise May Lead To Faster Recovery After Concussion

Translating Chronic Pain Research Into Practice: Chronic Pain and the Brain

The recent discovery that pain caused by a peripheral nerve injury can imprint itself in the central nervous system (centralized pain) ranks as one of the great advances in pain management. Although there has been some debate, these brain changes appear to be the result of chronic pain and not the cause. Centralized pain is often accompanied by symptoms of hyperarousal of the sympathetic nervous system, which can be used to help guide diagnosis and treatment of centralized pain.

The changing landscape of chronic pain research has yielded new ways to describe pain. The International Association for the Study of Pain (IASP) defines chronic pain as ongoing or recurrent pain that lasts beyond the usual course of acute illness or injury, or more than 3 to 6 months, and which adversely affects the individual’s well-being.1 IASP also offers a “simpler definition” of chronic or persistent pain: “pain that continues when it should not.” The Association defines central pain as pain due to a primary lesion in the spinal cord, brainstem, or cerebral hemispheres.1 The National Institute of Neurological Disorders and Stroke (NINDS) defines central pain syndrome as follows: “Central pain syndrome is a neurological condition caused by damage to or dysfunction of the central nervous system (CNS), which includes the brain, brainstem, and spinal cord. This syndrome can be caused by stroke, multiple sclerosis, tumors, epilepsy, brain or spinal cord trauma, or Parkinson’s disease.”2

These well-recognized terms should not be confused with the recently used description of centralized pain (CP) or central sensitization.3-5 In reality, all perceived pain is centralized. Pain arises from activation of nociceptors, the sensory receptors in skin, muscle, joints, and the viscera (exceptions being central pain syndromes), which then activate second order neurons in the CNS (spinal cord or brainstem). These, in turn, convey that “nociceptive information” to several sites in the brain, including eventually the cortex, where the conscious appreciation of the activated nociceptor is realized as pain. Therefore, most chronic pain states are driven by activation of nociceptors (or injured nerves) in peripheral tissue. The evidence in support of this derives from experiments in humans with fibromyalgia, irritable bowel syndrome, neuropathic pain, and bladder pain syndrome, in which peripheral blockage of input by local anesthetics disrupts the chronic pain for the duration of local anesthetic action.6,7

The discovery, however, that pain caused by a peripheral nerve injury can imprint itself in the CNS ranks as one of the great advances in pain management.8-10 Magnetic resonance imaging (MRI) studies recently have shown loss of grey matter density in patients with chronic pain.11-18 Although there has been some debate, these changes in brain volume appear to be the result of chronic pain and not the cause. In one study, researchers investigated 32 patients with osteoarthritis of the hip and found a decrease in grey matter in the anterior cingulate cortex, right insular cortex and operculum, dorsolateral prefrontal cortex, amygdala, and brainstem compared with normal controls.14 Ten patients from this study underwent total hip replacement surgery. After surgery, all 10 patients were pain free, and MRI studies showed increases in gray matter, suggesting that these brain abnormalities may be, at least partly, reversible when pain is successfully treated.

These imaging studies and published reports are enhancing our understanding of pain mechanism, and will, hopefully, lead to improved targeted pain medications.10,19 But how does the pain practitioner translate these investigational findings to clinical practice. It has been my experience that CP causes hyperarousal of the sympathetic component of autonomic nervous system (SNS).3,410,12 According to Latremoliere and Woolf, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations.4 At this time, the diagnosis of CP is a clinical one based on history and physical examination. This article will review the major signs and symptoms of SNS hyperarousal to help clinicians diagnose CP.

Mechanism of SNS Hyperarousal

The mechanism of SNS hyperarousal in CP is not well understood. A number of studies have shown that there is a loss of control of the efferent nerve pathways in CP.20-23 The loss of efferent control allows excess electrical impulses to travel from the brain to the periphery via the SNS. I like to think of this phenomenon as “uncoupling” the SNS from central brain control. A review of the autonomic nervous system is instructive. It has 2 components: the inhibitory, or parasympathetic, and the stimulatory, or sympathetic, systems (Figure 1). For unknown reasons, however, CP does not cause much hyperarousal of the parasympathetic system.

Hyperarousal of the SNS causes a wide variety of symptoms including nausea, diarrhea, urinary hesitancy, sweating, and anxiety or nervousness (Table 1). The release of epinephrine and norepinephrine from the adrenal glands accounts for some complaints of nervousness, muscle spasm, and anxiety but also may cause tremors, tics, and episodes of excess body heat. Restless leg syndrome (RLS), which is associated with peripheral neuropathy, also is a frequent complaint. According to NINDS, RLS is a neurological disorder characterized by “throbbing, pulling, creeping, or other unpleasant sensations in the legs and an uncontrollable, and sometimes overwhelming, urge to move them …. the sensations range in severity from uncomfortable to irritating to painful.”24

The hallmark of intractable, chronic pain is pain that is “24/7,” often accompanied by severe insomnia, fatigue, and depression. The intensity and perception of chronic pain is thought to be related to the pain-induced structural changes in the cells of the CNS.3,4,8,12 It is believed that this implanting is the result of pain stimulating glial cells to form excess neuroinflammation and the release of toxins such as glutamate.8-10 As CNS cells attempt to reform (neuroplasticity), the pain somehow becomes imbedded in the process (Figure 2).3,12 Fatigue and lack of energy, common complaints among pain patients, is probably related to chronic, constant overstimulation of the SNS with exhaustion and depletion of some neurotransmitters such as dopamine, serotonin, and norepinephrine. The presence of hyperarousal of the endocrine system requires laboratory testing.25-27

Physical Signs of SNS Hyperarousal

The physical signs of SNS hyperarousal are quite specific, objective, and extremely useful in determining the presence of CP (Table 2). As illustrated in Figure 1, there are a number of potential sympathetic “signs” I look for when examining a patient with chronic pain. These include dilated pupil size (mydriasis), elevation of blood pressure and pulse rate, and vasoconstriction (cold hands and/or feet). Sometimes there will be cold spots over the body, particularly over the spine or knee where there has been former tissue injury. Interestingly, if the patient has a pain flare with excess outpouring of catecholamines from the adrenals, they may report heat and an elevated body temperature, whereas the hands or feet may be cold. Hyperreflexia will be present, but it may not be uniform. Hyperhidrosis is present, and the best anatomical place to clinically spot and feel it is the skin under the eyes.

Partial Fallacy: You Can’t Measure Pain

There are old sayings “pain can’t be measured” and “you just have to take the patient’s word for it.” These are half-truths. Pain that has imprinted in the CNS, which now appears to affect a high proportion of the chronic pain population, will demonstrate objective, physical signs of SNS hyperarousal if the patient’s pain is poorly controlled. Every pain practitioner should develop some simple clinical techniques to routinely search for SNS hyperarousal. A simple protocol at the initial examination and at each follow-up visit is highly recommended. For example, I have a checklist for the signs of SNS hyperarousal on my intake forms and physical examination. Taking a patient’s blood pressure and pulse rate are routine at each follow-up visit. I also always shake hands with each patient during follow-up visits, in part to see if the patient has cold hands. I scan each patient’s face and pupil to look for pupillary dilation and hyperhidrosis under the eye. I use a small flashlight to check for dilated or constricted pupils.

Impact on Treatment

How does finding SNS abnormalities help one to decide how to treat the patient? In addition to taking a personal history, a quick assessment of SNS hyperarousal tells me if the patient has good pain control, and if dosages in the medication regimen need to be increased or decreased.27 Chronic overstimulation of the SNS may demand more treatment than the standard pain medications (ie, anti-inflammatory or opioid medications). Fatigue, insomnia, and depression are hallmarks of chronic pain and SNS hyperarousal. The addition of sleep medications, antidepressants, anti-anxiety agents, and neuropathic agents all will be necessary in various patients. Unfortunately, in some patients, risky agents such as the benzodiazepines, carisoprodol, and stimulants may be required—but on a case-by-case basis. Put another way, I consider recognition of hyperarousal of the SNS to be a down home, backbone of medication management.

Some of the symptoms and signs of chronic SNS hyperarousal are undoubtedly related to chronic release of epinephrine, norepinephrine, and other neurotransmitters. Consequently, there may be depletion of neurotransmitters such as serotonin and dopamine. This may account for some of the tremors, tics, and other symptoms that CP patients frequently report. Interestingly, the use of stimulants, such as dextroamphetamine or methylphenidate, may have a diabolic or counterintuitive effect on blood pressure and pulse rate. They may calm or depress the SNS rather than stimulate it because these agents are adrenergic (dopamine, norepinephrine) agonists and may substitute for depleted neurotransmitters.

Remember, SNS symptoms are a guidepost for the clinician to judge how a pain patient is doing. If a chronic pain patient does not have any SNS symptoms but complains of severe pain, the clinicians should not discount the patient’s report. There is no substitute for good, old fashion, clinical judgment.


Chronic, intractable pain is a catastrophic condition that causes immense suffering and debilitation. A great portion of the misery and impairment caused by CP is chronic hyperarousal of the SNS. Most of the classic symptoms of CP, particularly insomnia and fatigue, are directly related to this phenomenon. Physical signs of SNS hyperarousal include dilated pupils, hypertension, tachycardia, hyperreflexia, hyperhidrosis, and vasoconstriction usually manifested by cold hands or feet. In my opinion, it is essential to recognize hyperarousal of the SNS because it tells clinicians that the patient has poorly controlled pain and appropriately helps directs treatment. Routine assessment for the physical signs of SNS hyperarousal helps the practitioner objectively manage medications. In addition to analgesics, multiple other agents likely will be necessary to control hyperarousal of the SNS.

Last updated on: October 28, 2014
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