Mechanisms for Pain Caused by Incisions

Postoperative incisional pain is a unique and common form of acute pain. Because effective postoperative analgesia reduces morbidity after surgery, new treatments continue to be investigated. However, much of the scientific work to date on postoperative pain management has focused on regional analgesia and pharmacology. Much less effort has been dedicated toward studies of the mechanisms that subserve acute postoperative pain.1 Yet, it is through the study of mechanisms that a better understanding of incisional pain can be achieved and perioperative medicine will be advanced. There is ample evidence that pain caused by inflammation, nerve injury, or incision is based on different pathophysiologic mechanisms.2,3 This explains why many treatment strategies are efficacious only against specific types of persistent pain.2 Recognizing this gap between preclinical models of persistent pain and postsurgical pain, we have been interested in better understanding the mechanisms for pain caused by incisions. Therefore, we developed4 and characterized5 a rat model for postoperative pain. An incision made in the plantar aspect of the rat hindpaw causes persistent, reduced withdrawal thresholds to mechanical stimuli suggesting hyperalgesia (decreased pain threshold to suprathreshold stimuli). Primary hyperalgesia, enhanced pain to mechanical and thermal stimuli in the area of the incision, and secondary hyperalgesia, enhanced pain only to mechanical stimuli adjacent to the area of tissue injury, are present after a surgical incision in this model6 and in several clinical studies.7-9 Because primary hyperalgesia is caused by primary afferent nociceptor sensitization and secondary hyperalgesia is produced by sensitization of central neurons, peripheral and central sensitization likely contribute to pain after an incision. In agreement with this, Pogatzki et al.10 showed that A-delta and C fibers were sensitized by an incision and that the conversion of mechanical insensitive silent nociceptors to mechanically active fibers likely has a role in the maintenance of hyperalgesia after an incision. Furthermore, recording action potentials from dorsal horn neurons show that wide dynamic range neurons become sensitized after an incision and mediate the reduced withdrawal threshold observed in behavioral studies.11,12 In contrast to other more persistent and intense tissue injuries like inflammation or nerve injury, sensitization of dorsal horn neurons is maintained at least initially by excitation of primary afferents fibers (peripheral sensitization). 13 We investigated the role of excitatory amino acid receptors (EAA), N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA: alpha-amino-3-hydroxy5-methyl-4-isoxazole-propionic acid and kainate), for the development and maintenance of postoperative pain. Spinal NMDA receptor antagonists inhibit exaggerated pain behaviors in most models of persistent pain and are critical for activity-dependent plasticity, wind-up, and central sensitization. No effect on pain behaviors after plantar incision was observed14 in agreement with a recent clinical study.15 Surprisingly, intrathecal administration of non-NMDA receptor antagonists blocked painrelated behaviors after incision.16 Clinical studies have examined the effect of AMPA-kainate receptor antagonists in patients with persistent pain17; more studies on this group of EAA receptors will follow. Other spinally administered drugs producing analgesia in this model include L-type calcium channel receptor antagonists,18 alpha-2 adrenoceptor antagonists,19 and adenosine receptor agonists.20 Because central sensitization may be important for postoperative pain, many have proposed that a blockade of noxious input to the spinal cord before From the Department of Anesthesia and Intensive Care, University of Muenster, Muenster, Germany; and the University of Iowa, Iowa City, Iowa. Accepted for publication April 6, 2002. Reprint requests: Peter K. Zahn, M.D., Department of Anesthesia and Intensive Care Medicine, University of Muenster, Albert Schweitzer Str. 33, 48149 Muenster, Germany. © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2705-0014$35.00/0 doi:10.1053/rapm.2002. 35155