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  1. Understanding the mechanisms underlying chronic pain requires knowledge of the neuroanatomy, neurochemistry, and neurophysiology of nociception and central pain processing.

  2. Generation of pain hypersensitivity results from changes in the function, chemistry, and structure of both the peripheral and central nervous systems.

  3. Pain can be categorized into the following broad etiologic groups: nociceptive pain is associated with an ongoing nociceptive stimulus and reflects minimal central modulation of the painful stimulus; inflammatory pain describes pain due to tissue inflammation; neuropathic pain results from injury of the peripheral or central nervous system; dysfunctional pain refers to pain due to abnormal functioning of the nervous system, despite the absence of an identified insult.

  4. Nociception serves a protective function that is important from an evolutionary perspective. However, chronic pain—especially neuropathic pain and dysfunctional pain—do not serve such a protective role and result instead from a pathologic condition of the nervous system. In these circumstances, chronic pain is a disease.

  5. As an injury heals, pain can dissipate with resolution of tissue injury and inflammation; alternatively, pain can persist and become independent of peripheral stimulation. The independence of ongoing stimulus reflects the marked pathologic changes that persistent pain effects on the nervous system.

  6. Different mechanisms are responsible for different types of pain, and therefore the rational and successful treatment of pain requires diagnostic and therapeutic modalities that reflect the specific molecular mechanisms.


The major function of the pain system is to protect the body from injury. Its evolutionary importance is underscored by the disfiguring injuries and frequent early death of people who have the rare recessive condition congenital insensitivity to pain. The importance of pain from a clinical perspective led the Joint Commission on Accreditation of Healthcare Organizations to declare that pain level constitutes a fifth vital sign. Unlike other diagnostic signs, the pain score is subjective, thus making pain difficult to study clinically. The initial step in pain signaling, nociception, was defined by Sir Charles Sherrington a century ago as the sensory detection of a noxious event or a potentially harmful environmental stimulus.1 However, pain represents the integration of a wide range of inputs and modulations that span the neuraxis, from nociception in the distal periphery to complex processing of pain in the brain (Fig. 89-1). Consistent with this, psychologic trauma can cause pain that is perceived much in the same way as that associated with an injured extremity. And yet despite the similar experience of pain, the mechanisms underlying these 2 conditions must be different, at least in all but the highest-level representations of the pain. Indeed, we now know that virtually all chronic pain is fundamentally different from "nociception" in the sense of the simple detection of an acute noxious stimulus and its unmodulated transmission to the brain. Rather, chronic pain is the result of amplified and broadened inputs into a sensitized central system. This chapter focuses on mechanisms that generate and maintain pain.


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