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Preemptive analgesia as a concept began over 90 years ago, when Crile and Lower proposed that blocking noxious signals prior to a surgical incision may lead to some degree of central nervous system (CNS) protection against postoperative pain, though at that time the mechanism remained unclear.1 Crile believed that a combination of locoregional blocks and general anesthesia (GA), especially when the blocks were performed in advance of the painful stimulus, favorably influenced postoperative recovery compared with GA alone. Crile concluded that “patients given inhalational anesthesia still need to be protected by regional anesthesia otherwise they might incur persistent central nervous system changes and enhanced postoperative pain.”2 The notion that the CNS “modulates” afferent pain signals before being perceived by the individual was furthered in 1965 when Melzack and Wall proposed their gate theory.3 This landmark paper suggested that incoming pain signals are subject to inhibition by either competing nonpainful afferent input at the same spinal level or from supraspinal descending pathways. For example, rubbing one's foot after stubbing your toe lessens the perception of pain due to the “closure” of a theoretical gate in the substantia gelatinosa that allows for only one type of afferent impulse to be transmitted to the CNS. However, this theory did not incorporate long-term changes in the CNS following nociceptive input and to other external factors that impinge on the individual. It is now recognized that nociceptor function is dynamic and may be altered following tissue injury. Repetitive stimulation of small-diameter primary afferent fibers generates a progressive increase in action potential discharge and increased excitability of both peripheral and CNS neurons, an event termed sensitization or “wind-up.” This is the mechanism by which pain may be prolonged beyond the duration normally expected with an acute insult. Furthermore, this increased excitability in the CNS has the capacity to permanently alter spinal cord function leading to the development of chronic pain following an acute injury. Preemptive analgesia has been proposed as a method of decreasing postoperative pain by the prevention or attenuation of this wind-up phenomenon.


Physiology of Central & Peripheral Sensitization


The perception of pain is not a hard-wired mechanism, wherein stimuli are always transmitted and processed in an identical manner each time. In fact the CNS exhibits a great deal of plasticity. The processing of pain signals is now recognized to be a complex physiologic cascade that involves dozens of different neurotransmitters and chemical substrates at several different anatomic locations. Operative procedures produce an initial afferent barrage of pain signals and generate a secondary inflammatory response, both of which contribute substantially to postoperative pain. The signals have the capacity to initiate prolonged changes in both the peripheral and central nervous system that will lead to the amplification and prolongation of postoperative pain. Peripheral sensitization, a reduction in the threshold of nociceptor afferent peripheral terminals, is a result of inflammation at the site of surgical trauma.4...

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