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