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Most often, tissue damage is associated with complaints of pain, although neither the magnitude of the original injury nor the "visible" nature of it correlates with the subsequent intensity of the pain. In the case of inflammatory pain, it is well understood that tissue damage from chemical, mechanical, or thermal stimuli results in the release of inflammatory mediators and pro-inflammatory cytokines from the cells that sensitize and/or stimulate free nerve endings, initiate the coagulation cascade, and activate the immune system.[8] [11] [15] The ensuing lowering of the activation threshold of the receptors for pain at the site of injury (called peripheral sensitization) results in the bombardment of the spinal cord with continuous noxious input via A-delta and c-fibers. Additionally, under the duress of intense inflammatory pain (or lower-intensity but continuous neuropathic pain), A-alpha and A-beta fibers are induced to participate in the transmission of pain signals. This is significant, given that their input is not filtered in the spinal cord in the same way as A-delta and c-fibers, nor can it be dampened or modified as effectively with classic analgesic medications such as opioids. It is believed that the continuous nature of the input provokes changes in the chemical milieu in the spinal cord and triggers structural reorganization (referred to as plasticity) that raises the potential for establishing neuropathic pain. Thus, at the very time there is enhanced noxious input, there is an induction of decreased central inhibition that would ordinarily modify the input and the subsequent CNS response.
The dorsal root ganglion (DRG) represents a passageway for much of the sensory input into the spinal cord. Because the DRG is subject to the enormous influences of chemical mediators, sensitization and amplified responses are common even at this level.[17] There can be a number of axon projections from one DRG into various levels of the spinal cord. Particular attention has been focused upon the layering of axon termination in the lamina of the dorsal horn of the spinal cord, the pharmacology of which is increasingly being determined.[18] Much of the A-delta and c-fiber input terminates in layers I, II (the substantia gelatinosa), and V. Peptides such as substance P, somatostatin, cholecystokinin, enkephalins, glutamate, aspartate, and VIP act as neurotransmitters—their release continues the propagation of the neural response (and should provide the opportunity for interruption thereof with selective blocking agents or antagonists). Wide dynamic range (WDR) neurons located primarily in layers I and V are an important group of neurons in that they receive input from nociceptive-specific and non-specific afferent fibers.
When repetitive stimulation of dorsal horn neurons involved in the pain response occurs, the frequency of discharge can be shown with neurophysiologic techniques to increase.[11] [15] [19] This is called sensitization or "wind-up." The activation of N-methyl-D-aspartate (NMDA) receptors results in spinal cord neurons being more reactive to all input and decreases the neuronal sensitivity to opioid agonists.[20] The clinical correlate is that less peripheral stimulation is required to activate a "pain response" in the CNS. Thus, stimuli that are not normally painful, (i.e., lightly stroking the skin) cause patients agony because the CNS response is augmented by maladapted changes in the processing of sensory input—the touch hurts and the pain lingers even when the direct stimulation is stopped because of the hyperirritability of the nervous system and the failure of the usual modulatory systems to dampen the reactivity.[21]
The CNS response in the spinal cord is sensitized by algesic mediators, complicating the management of pain, as patients develop allodynia (non-painful stimuli provoke a painful response), hyperesthesia (low threshold, painful stimuli yield a pain response), and hyperpathia (a painful stimulus provokes an enhanced response). [7] Much contemporary treatment is aimed at blocking the sensitization of the CNS with drugs that interrupt activation of NMDA and adenosine monophosphate aspartate (AMPA) receptors.[21] [22]
What happens in the more central projections of the nervous system from the spinal cord is still not well understood. Input travels in the spinothalamic tract (STT) from lamina I, V, and VII and crosses the midline to ascend in the anterolateral quadrant of the spinal cord to nuclei in the thalamus and brainstem.[15] [23] Near the thalamus the STT divides into a lateral portion, also called the neospinothalamic tract (associated with sensory/discriminative aspects of pain perception) and a medial portion, called the paleospinothalamic tract (associated with the affective/motivational aspects of pain perception). The last-mentioned tract has numerous synapses with the reticular formation of the brainstem, the medial thalamus, the periaqueductal gray matter, and the hypothalamus. Sensory input is processed in the thalamus and passes to the cerebral cortex. This input to higher CNS centers and the fact that there are descending pain modulatory systems foster emphasis on patient education as an important factor in the patient's response to treatment, because these are entities that can be utilized in treatment.
Physiologically, it has been discovered that opioids interplay at the rostral ventromedial medulla within the descending modulatory neural system. There is growing evidence that the maintenance, but not the initiation, of neuropathic pain and the hyperalgesia caused eventually by chronic opioid use is mediated here. [24] [25] Also significant is the profound insight provided by Melzack and Wall in their presentation of the gate control theory in 1965.[26] This theory not only proposed a dynamic gating mechanism in the nervous system for dampening and modifying noxious input but also envisioned the descending limb of the neural response in which a positive impact on incoming sensory input was possible. Beyond the scientific contribution, the gate control theory opened many clinicians' minds by providing a theoretical construct in which explanations for many seemingly bizarre pain phenomena were feasible.
When a patient manifests neuropathic pain, the somatic and/or sympathetic and/or visceral components of the pain have persisted for weeks to months. Visits to physicians and diagnostic tests have not accurately determined the cause of the pain nor has effective therapy been provided. The marked change in the patient's attitude about recovering contaminates everything they do and the physical deconditioning validates their decreasing functional status and feelings of low self-worth. Frustration with the health care system and the adverse impact of "the pain" interfere with the patient's desire to maintain occupational and social responsibilities. Eventually illness behaviors can become entrenched, further complicating the patient's willingness to make the necessary changes in treatment to restore the pre-pain lifestyle and relationships.[8] [12] [13] [15]
As time passes, the domains of the patient affected by pain exceed the neurophysiologic and psychosocial and grow to include the ethnocultural, affective, and cognitive dimensions. The extent of the pain becomes so great that no single doctor can be expected to assess the patient adequately and no single treatment can be expected to be helpful. The significance of the structural reorganization and phenotypic alteration within the CNS (neural sprouting, increased sodium channels and novel ion channel expression, upregulation of NMDA receptors, and gene expression) is hard to quantitate but lends credibility to the understanding that, even though the inciting event for the pain is gone, the CNS consequences of the pain event may not have been reset to normal.[20] [21] [22]
Thus, complaints of pain persist. Petrenko and associates highlighted and broadened the very important evolving role that NMDA receptors have in pain. [22] They noted that "... NMDAR [N-methyl-D-aspartate receptors] located in peripheral somatic tissues and visceral pain pathways play an important role in nociception ... therefore each level should be considered as a potential target for therapeutic intervention."[22] Clinically, a characteristic of neuropathic pain based upon the physiologic plasticity includes ongoing pain in the absence of tissue injury; pain projected into areas of abnormal sensation; spontaneous and paroxysmal pain; the presence of allodynia, hyperpathia, and dysesthesia; a delay in the onset of pain after stimulation; and prolonged pain after the stimulus has been removed.[14] [21] [22]
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