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by minutes to hours.38 Central sensitization is associated with a reduction in central inhibition, spontaneous DH neuron activity, the recruitment of responses from neurons that normally only respond to lowintensity stimuli (i.e., altered neural connections), and expansion of DH neuron receptive fields.27,60,67,76-78 Clinically, these changes may manifest as: 1) an increased response to a noxious stimulus (hyperalgesia), 2) a painful response to a normally innocuous stimulus (allodynia), 3) prolonged pain after a transient stimulus (persistent pain), and 4) the spread of pain to uninjured tissue (i.e., referred pain).60,79 In contrast to hyperalgesia caused by peripheral mechanisms (i.e., primary hyperalgesia), such secondary hyperalgesia extends beyond the region of injury.48,80 b. Clinical implications Sensitization is likely responsible for most of the continuing pain and hyperalgesia after an injury.81 This sensitivity may be due to “normal” noxious input from injured and inflamed tissue or “abnormal” input from injured nerves or ganglia. In the former case, sensitization serves an adaptive purpose. That is, the hyperalgesia and allodynia encourage protection of the injury during the healing phase. However, these processes can persist long after healing of the injury in the setting of chronic pain. Central sensitization plays a key role in some chronic pain, especially pain induced by nerve injury or dysfunction (i.e., neuropathic pain). It explains why neuropathic pain often exceeds the provoking stimulus, both spatially and temporally.48,60 Central sensitization also explains the longstanding observation that established pain is more 8 Pain: Current Understanding of Assessment, Management, and Treatments Section I: Background and Significance eEarly transient changes include removal of the voltage-dependent magnesium blockade of NMDA receptors. This permits glutamate to activate NMDA receptors, with subsequent temporal summation of slow synaptic potentials that manifests as wind-up.27,62-63 f Central sensitization reflects a complex series of changes that may begin with the release of excitatory substances (e.g., glutamate, substance P) from cells following noxious stimulation. These substances activate NMDA and non-NMDA (NK) receptors, which increases intracellular calcium levels67-70 and activates calciumdependent intracellular kinases.38,71 These kinases break down arachidonic acid (releasing byproducts)72 and phosphorylate ion channels and NMDA receptors. Potential consequences of these changes include altered synaptic transfer and gene expression (e.g., c-fos).27,60,73-74 Collectively, these changes may promote long-lasting increases in DH neuron excitability (i.e., central sensitization). difficult to suppress than acute pain.13,75,82-83 In contrast to nociceptive pain, neuropathic pain is often unresponsive or poorly responsive to NSAIDs and opioids.84-85 However, it may respond to antiepileptic drugs, antidepressants, or local anesthetics.86 9. What Is Nociceptive Pain? Pain that is classified on the basis of its presumed underlying pathophysiology is broadly categorized as nociceptive or neuropathic pain.87 Nociceptive pain is caused by the ongoing activation of A-δ and C-nociceptors in response to a noxious stimulus (e.g., injury, disease, inflammation).88 Pain arising from visceral organs is called visceral pain, whereas that arising from tissues such as skin, muscle, joint capsules, and bone is called somatic pain. Somatic pain may be further categorized as superficial (cutaneous) or deep somatic pain (Table 1). In contrast to neuropathic pain, the nervous system associated with nociceptive pain is functioning properly. Generally, there is a close correspondence between pain perception and stimulus intensity, and the pain is indicative of real or potential tissue damage. Differences in how stimuli are processed across tissue types contribute to the pain’s varying characteristics (Table 1).22 For example, cutaneous pain is often described as a well-localized sharp, pricking, or burning sensation; deep somatic pain, as a diffuse dull or aching sensation; and visceral pain, as a deep cramping sensation that may be referred to other sites (i.e., referred pain).88 Associated clinical pain states (e.g., hyperalgesia, allodynia) reflect sensitization (see I.B.7-8).88,90 10. What Is Neuropathic Pain? Neuropathic pain is caused by aberrant signal processing in the peripheral or central nervous system.g,96 In other words, neuropathic pain reflects nervous system injury or impairment. Common causes of neuropathic pain include trauma, inflammation, metabolic diseases (e.g., diabetes), infections (e.g., herpes zoster), tumors, toxins, and primary neurological diseases.81 Neuropathic pain can be broadly categorized as peripheral or central National Pharmaceutical Council 9 Section I: Background and Significance Table 1. Examples and Characteristics of Nociceptive Pain Superficial Somatic Pain Deep Somatic Pain Visceral Pain Nociceptor location Skin, subcutaneous tissue, Muscles, tendons, joints, Visceral organsa and mucous membranes fasciae, and bones Potential stimuli External mechanical, Overuse strain, mechanical Organ distension, muscle spasm, chemical, or thermal events injury, cramping, ischemia, traction, ischemia, inflammation Dermatologic disorders inflammation Localization Well localized Localized or
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