Chronic Pain

Pathophysiologic Chronic Pain

The International Association for the Study of Pain has defined the word pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

While the sensation of pain is important from an evolutionary standpoint, a warning system signaling injury or further damage, pain can transform a beneficial sensory phenomenon to a pathologic and not easily relived state know as chronic pain. In chronic pain patients, pain is less a symptom than a proper disease of the nervous system. Chronic pain has been described as pain that persists beyond the expected time of healing. However, this description is unsatisfactory because rates of healing and factors associated with it are poorly understood. Plus, pain disorders are not necessarily linked to specific injuries. Some chronic pain conditions, such as myofascial and temporomandibular disorders (TMDs), fibromyalgia (widespread pain), and irritable bowel syndrome do not often involve recognizable peripheral insult and are more and more described as central sensitivity syndrome.

In a general sense, chronic pain is sometimes simply described as pain that persists for three to six months or more. With this simple descriptive definition, chronic pain has become an epidemic with astounding economic and psychosocial consequences. The financial burden alone is startling. Chronic pain is estimated to cost in excess of US $1 trillion annually in developed countries. Chronic pain reduces quality of life, often causes physical disability, and is a serious risk factor for suicide. Therefore, providing pain management is essential in medical and dental care. Furthermore, approximately two out of three chronic pain patients suffer from comorbid conditions such as mood alteration, clinical insomnia, and depression, which can be associated with a variety of negative health consequences.

Mechanisms of Persistent Pain

The pain system (nociceptive processing) contains ascending and descending systems that function in parallel. Ascending pain transmission is the process that affords the brain with information about potential tissue damage once the cascade of neural signals is set in motion. Peripheral transmission of nociceptive signals occurs by two distinct groups of peripheral fibers, generally termed primary afferent fibers. Cold and well-localized pain sensations are mediated by fast-conducting myelinated Alpha-Delta and Alpha-Beta fibers. Unmyelinated and more slowly conducting C fibers transmit nociceptive signals produced by mechanical stimuli, noxious heat, or by poorly localized stimuli. In general, Alpha-Delta fibers are thought of as contributing to first-pain sensations, which are often described as “sharp” or “pricking.” In contrast, activation of C fibers tends to produce diffuse “aching” or “burning” sensations. Sensory receptors such as these are common to almost all multicellular animals and work together in determining the conscious experience of pain.

These ascending signaling systems do not operate in isolationand they are subject to many local modulatory factors such as substance P, potassium ions, histamine, prostaglandins, bradykinin and leukotrienes. These substances all have the potential to induce changes in the peripheral receptors and primary afferent fibers. These changes include a reduced activation threshold, expansion of receptive fields, generation of spontaneous activity, expansion of receptive fields and recruitment of normally inactive, or silent, nociceptors. These and other similar changes create peripheral sensitization, which results in an increased nociceptive signal to the spinal cord.

Peripheral and central sensitization

Peripheral sensitization is reduced pain threshold (eg, increasing the probability of perceiving pain) brought about by increased responsiveness of peripheral nerve ending, or nociceptors, such as those in skin, muscle, or joints. Most people have experienced the sensation. For example, normally nonpainful touch may become quite painful on sunburned skin. This is termed allodynia. Peripheral sensitization occurs because of the release of inflammatory chemicals and transduction proteins at the site of tissue damage, which in turn alters pain sensitivity through increased responsiveness of the peripheral nociceptors and fibers.

The repetitive or sustained activation of pain fibers associated with chronic pain can be approximated under controlled conditions in the laboratory. It is hypothesized that repetitive activation of pain fibers in states of chronic pain may alter the function and activity of central pain pathways and central processing sensory information linked to nociception. This process is termed central sensitization. It is produced and maintained by neuromodulators that augment transmitter and receptor activity or efficacy in the spinal cord and brain, prolonged afferent nociceptive input induces an increase in N-methyl-D-aspartate activity in the dorsal horn of the spinal cord, and induces Alpha-Beta fibers to establish functional connections with pain pathways in the spinal cord, and induces glial cells to release proinflammatory cytokines throughout the CNS.Curatolo M, Arendt-Nielsen L, Petersen-Felix S. Central hypersensitivity in chronic pain: mechanisms and clinical implications. Phys Med Rehabil Clin North Am 2006;17:287-302.

Collectively, the complex process of central sensitization produces tenderness, hypersensitivity,, and pain in an expanded area beyond the site of tissue damage. There is increasing evidence that central sensitization plays a role in chronic pain syndrome, including widespread musculoskeletal pains, fibromyalgia, irritable bowel syndrome, and myofascial and TMD pains.

Ascending and descending influences on nociception and pain

The integration of nociception in the perception of and reaction to pain is dependent on activation of parallel ascending pathways from spinal cord to the upper brain.

The two main pathways are:

1) the spinothalamic tracts for sensory processing of nociception, which include various thalamic relays and project to the sensory cortex

2) the spinolimbic tracts for emotional assessment of the emotional dimension of the pain experience, which project to the accumbent, amygdala, hypothalamus, insular cortex, cingulate cortex, and frontal cortex. In acute or experimental conditions, the activation of such pathways is concomitant with the activation of descending influences to alleviate nociception and reduce the emotional burden of pain; in chronic pain states, such mechanisms may be altered.

Under normal conditions, the overexcitement of spinal modulators is countered by local mechanisms and/or descending pain-inhibitory systems.  In response to the perception of pain, multiple brain regions of the spinal cord. However, dysregulation in this descending pain-modulatory circuitry is hypothesized to play an etiologic role in the chronic pain conditions of many patients. In part, this process constitutes the pain gate, which has been theorized (in the gate control theory) to modulate transmission of pain-related signals at spinal and brainstem levels. -Melazck R, Wall PD. Pain mechanisms: A new theory. Science 1965;150:971-979

Evidence for central hypersensitivity in chronic pain patients

There is consistent and ample evidence that many chronic pain syndromes, including somatic, visceral, neuropathic, and inflammatory chronic pain, are characterized by generalized hyperalgesia (an increased reactivity to pain) and diminished effectiveness of descending pain inhibition, which may result in hyperalgesia. Bonica JJ. Neurophysiologic and pathologic aspects of acute and chronic pain. Arch Surg 1997;112:750-761

It is not at all surprising that pain conditions such as fibromyalgia, TMDs, headaches, rheumatoid arthritis, complex regional pain syndrome, irritable bowel syndrome, and many others enhance pain sensitivity at the sites of pain complaints. Yet, this observation alone cannot distinguish between peripheral contributions to altered pain responsiveness and central hypersensitivity to pain. Currently, there is ample evidence that all of those conditions, and many others, are characterized by enhanced sensitivity to pain at anatomic sites that are distant from the site of pain and are not considered to be involved in the local pathophysiology of the condition. For example, patients with TMDs show reduced pressure pain thresholds at the finger, hand, and leg.


The factors contributing and influencing to the development of chronic pain are multiple and complex. Alterations in peripheral and CNS processing of pain-related information play a key role. Identification of premorbid biologic (eg, genetic predisposition) or behavioral (dysfunctional coping strategies) risk factors for persistent pain is of extreme importance.  This identification may lead to prevention efforts or targeted early interventions to reduce the incidence of chronic pain.

Highly pain-sensitive individuals seem to be at high risk of morbidity; tailored intervention may reduce their relatively elevated likelihood for developing chronic pain. Given the ease of assessing these factors, such as premorbid pain sensitivity, future clinical practice may potentially sizable benefits to the patients.

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