Clinical ® PAIN Updates INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN® Volume XIII, No.2 June 2005 EDITORIAL BOARD Editor-in-Chief Daniel B. Carr, MD The Challenge of Preemptive Analgesia Internal Medicine, Endocrinology, Anesthesiology USA Advisory Board 1 Elon Eisenberg, MD n 1988, Wall reviewed emerging data showing that analgesia before surgical Neurology I incision or amputation decreased postsurgical pain or reduced the incidence of Israel phantom pain, respectively, and decreased the amount of postoperative analgesic James R. Fricton, DDS, MS Dentistry, Orofacial Pain needed. Wall’s publication may be the first review of “preemptive analgesia,” USA which is defined as intervention preceding surgery for the purpose of preventing Maria Adele Giamberardino, MD or decreasing postsurgical pain by preventing central sensitization. To attain Internal Medicine, Physiology Italy preemptive analgesia, however, several critical principles must be applied suc- Cynthia R. Goh, MB BS, FRCP, PhD cessfully. Failure to apply all of these principles may lead to inadequate postsur- Palliative Medicine Singapore gical analgesia. In addition, in patients with pre-existing pain before surgery, Alejandro R. Jadad, MD, PhD preemptive analgesia is unfeasible because central sensitization has already oc- Anesthesiology, Evidence-Based curred due to presurgical pain. This issue of Pain: Clinical Updates surveys the Medicine and Consumer Issues Canada basis for, and challenges facing, preemptive analgesia and presents a practical Andrzej W. Lipkowski, PhD, DSc method for its successful practice. Neuropharmacology and Peptide Chemistry Poland Central Sensitization and Wind-up Patricia A. McGrath, PhD Psychology, Pediatric Pain Canada In response to nociceptive impulses, c-fos, a gene expressed rapidly in many Mohammad Sharify, MD types of cells in response to various stimuli, is expressed in spinal dorsal horn Family Medicine, Rheumatology and supraspinal neurons. In these and other cells along nociceptive pathways, Iran c-fos expression serves as a marker for cellular activation, i.e., nociception. C-fos Bengt H. Sjolund, MD, PhD Neurosurgery, Rehabilitation expression is followed by central sensitization—a lowering of the threshold for Sweden responses to further stimuli and hyperalgesia.2,3 In addition, electrophysiological Maree T. Smith, PhD Pharmacology experiments have shown that repetitive low-frequency stimulation of C fibers Australia (0.5–2 Hz) lowers the threshold for activation of spinal cord neurons and pro- Harriët M. Wittink, PhD, PT longs their discharge following brief stimuli (wind-up).2,3Both central sensitiza- Physical Therapy The Netherlands tion and wind-up intensify pain perception, and both depend on activation of N-methyl-D-aspartate (NMDA) receptors.2,3 In other words, pain memories im- Production Elizabeth Endres, Copy Editing printed within the central nervous system by NMDA-receptor activation produce Kathleen E. Havers, Executive Assistant 4 Juana Braganza Peck, Layout/Graphics hyperalgesia and contribute to symptoms such as allodynia. Therefore, postsur- gical pain may in theory be preventable by presurgical nociceptive blockade with epidural anesthesia and an epidural opioid (anesthesia/analgesia). In animal experiments, c-fos expression, central sensitization, and wind-up do not occur if UPCOMING ISSUES nociceptive blockade is applied prior to the nociceptive event.2,3 These findings suggest that presurgical blockade of nociception may prevent postsurgical wound Visceral Pain pain or pain hypersensitivity in clinical surgery, thus providing preemptive anal- Genetic Influences gesia as advocated by Wall.1 Indeed, within a decade of the introduction of local Pain and Aging anesthetic techniques for regional analgesia, a similar hypothesis had been advanced by Crile.5 Supported by an educational grant from Endo Pharmaceuticals Inc., USA Three Critical Principles Postsurgical Central Sensitization Achieving successful preemptive analgesia is challenging. Many postsurgical stimuli, including movement and wound Central sensitization is easily initiated even by trifling nocicep- care of the surgical incision, can establish central sensitization tive impulses6 that can occur when an anesthesiologist neglects by themselves. Especially after open-chest surgery, repeated analgesia during surgery—even if briefly or to a small degree. respiratory efforts and intermittent abrupt movements such as In that case, preemptive analgesia will fail. To attain successful coughing or sneezing stimulate the skin, muscles, pleura, lungs, preemptive analgesia, “complete analgesia” must be (1) deep and mediastinum. These movements can easily trigger postsur- enough to block all nociception, (2) wide enough to cover the gical central sensitization. Furthermore, intercostal nerves are entire surgical area, and (3) prolonged enough to last throughout sometimes injured during surgery, commonly leading to inter- surgery and even into the postoperative period. When careless- costal causalgia (complex regional pain syndrome, type II).9 ness results in failure to achieve all three critical principles, Therefore, meticulous postsurgical analgesia can be a crucial preemptive analgesia is likely to fail. component of perioperative preemptive analgesia. Clearly, ef- fective treatment must protect patients from postsurgical pain. Presurgical Pain Overcomes Preemptive Analgesia Multiple Nerve Innervations When patients have pre-existing pain well in advance of surgery, presurgical analgesic interventions in the immediate Surgical sites in the abdomen and chest have redundant presurgical period cannot have a postsurgical analgesic effect. innervation via somatic and autonomic nerves. Both pathways In such cases, presurgical intervention does not yield preemp- transmit nociceptive signals to the thalamus. Somatic nerves tive analgesia because central sensitization has already begun (except for the phrenic nerve), sympathetic nerves, and sacral long before surgery.7 In operations for trauma such as bone parasympathetic nerves enter the spine at thoracic levels or fractures or during inflammatory states such as appendicitis, lower, whereas the phrenic and vagus nerves enter the cervical peritonitis, and osteoarthritis, residual inflammation after sur- spine and brainstem, respectively. The phrenic nerve generally gery produces lingering pain and ongoing central sensitization.8 controls motor and sensory function of the diaphragm. In addi- In the above circumstances, any interventions just before tion, sensations from the trachea, bronchi, pericardium, pleura, surgery are already too late; analgesia throughout surgery, esophagus, esophagocardial junction, and subphrenic perito- “postemptive analgesia,” is limited to maintaining the presur- neum are also conveyed via the phrenic nerve. Although the gical sensitization level. With inadequate operative analgesia, phrenic innervation is segmental in the early embryo, it devel- intrasurgical nociceptive impact builds upon the presurgically ops broader visceral projections during later development. initiated sensitization, and the magnitude of sensitization is Consequently, heterosegmental innervations are formed. In reset even higher.7 open-chest surgery or subphrenic abdominal surgery, the Table 1. Single and multiple innervations of common somatic and visceral surgical sites Innervation Organs Segmental Heterosegmental Head, face Cranial nerves Neck, nape Cervical nerves Body surface Spinal nerve Extremities Spinal nerve Chest Esophagus Thoracic nerve Phrenic nerve Vagus nerve Trachea, bronchus Thoracic nerve Phrenic nerve Vagus nerve Lung Thoracic nerve Phrenic nerve Vagus nerve Pleura Thoracic nerve Phrenic nerve Vagus nerve Heart Thoracic nerve Vagus nerve Pericardium Thoracic nerve Phrenic nerve Vagus nerve Diaphragm Thoracic nerve Phrenic nerve Vagus nerve Abdomen Subphrenic peritoneum Thoracic nerve Phrenic nerve Vagus nerve Esophagocardial junction Thoracic nerve Phrenic nerve Vagus nerve Abdominal organs Thoracic nerve Vagus nerve Peritoneum Thoracic nerve Vagus nerve Mesenterium Thoracic nerve Vagus nerve Retroperitoneal organs Thoracic nerve Vagus nerve Urogenital organs Lumbosacral nerve Vagus nerve 2 surgical area receives three-fold innervation from the spinal, vagus, and/or phrenic nerves (Table 1). Total regional anesthe- sia/analgesia covering the surgical area cannot be achieved with routine spinal or epidural analgesia, nor do such techniques ablate the stress hormone response to these operations.10 Thus, supplemental analgesia is required to silence the vagus and phrenic nerves in preemptive analgesia with regional anesthe- sia/analgesia. Animal Experiments Those who question the utility of preemptive analgesia often state that the technique is reliable in animal experiments but has variable results in clinical studies. The disparity between animal and clinical study results can be explained by important differences in study design. First, experimental animals typically have no pre-existing Fig. 1. Primary nociceptive transmission in the spinal cord. Primary pain, whereas many surgical patients present with presurgical afferent nociceptive input is transmitted via AMPA, neurokinin-1 pain. Second, in experimental animals, the stimulus is typically (NK1), and calcitonin gene-related peptide (CGRP) synapses, whose applied to the extremities or the tail, which are only segmentally signals work their way to the thalamus. Glutaminergic (NMDA) synapses do not participate significantly in primary