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 nociceptive innervated, whereas clinical surgical sites are diverse and transmission, but instead play a crucial role in spinal sensitization. include areas that receive multiple innervations. Third, animal Accordingly, even after complete NMDA blockade in the spinal cord, procedures are typically shorter than clinical surgical proce- primary afferent nociceptive information is transmitted to the dures; longer surgical procedures increase the risk that analgesia thalamus. NMDA antagonists thus have an antihyperalgesic rather than an analgesic effect in the spinal cord. may not be thoroughly maintained throughout the entire opera- tion. Because preemptive analgesia is unlikely to succeed with- out careful attention to detail and since clinical studies have an Ketamine is an effective treatment for central pain and thalamic increased risk of failure to adhere to the critical principles pain,12 but it has no analgesic effect in patients with cerebral described above, variable clinical results carry less weight than dysfunction13 or in decerebrate animals.14 These facts suggest positive animal findings. that ketamine works supraspinally as an analgesic and acts as a central (spinal and supraspinal) antihyperalgesic agent.2-4,15 Practical Preemptive Analgesia Visceral pain via the vagus nerve is transmitted to the medulla and initiates central sensitization.16,17 Therefore, a combination Several approaches for providing preemptive analgesia of epidural anesthesia/analgesia (acting segmentally) and intra- have been explored without satisfying results. Analgesia with venous low-dose ketamine (acting heterosegmentally) is appro- nonsteroidal anti-inflammatory drugs alone is not sufficiently priate for preemptive analgesia and can avoid the side effects deep to block all nociception. Subcutaneous infiltration alone such as protracted sedation and respiratory inhibition seen with with a local anesthetic is not wide enough to cover the entire opioids.18 Of course, these drugs must be applied continuously surgical area. Interventions provided only once before the surgi- from before the incision until after skin closure (Table 2). cal incision do not usually maintain their analgesic effect through surgery. Epidural anesthesia alone may fail to block all of the nerves innervating the surgical area. Misconceptions Table 2. Dosages of representative spinal and supraspinal about the proper application of anesthetics and analgesics have analgesic drugs for preemptive analgesia continued to cause confusion about the effectiveness of pre- emptive analgesia. Initial Continuous How does one achieve effective preemptive analgesia? In Drug Route Dose Dose a surgical area with segmental nerve innervation only, epidural Epidural analgesia anesthesia/analgesia, spinal block, or nerve block are appropri- Morphine (µ-agonist) Epidural 3 mg 1–2 mg/h ate for preemptive analgesia. In areas with multiple innerva- Buprenorphine (partial -agonist) Epidural 0.1 mg 0.02–0.03 mg/h tions, analgesia with a systemic opioid will reduce not only µ Eptazocine (κ-agonist, segmental but also heterosegmental nociception. The use of µ-antagonist) Epidural 15 mg 2.5–5.0 mg/h high doses of systemic opioids to achieve systemic analgesia Supraspinal analgesia is not recommended, however, because postoperative sedation, Ketamine Intravenous 1 mg/kg 0.5 mg·kg-1·h-1 constipation, urinary retention, and respiratory disturbances Note: As with other mixed κ-agonist/µ-antagonist drugs, eptazocine should can result. not be administered to patients who have been maintained chronically on a Ketamine is a general anesthetic at high doses and an anal- regimen of µ-agonist agents such as morphine, oxycodone, or fentanyl. Doing gesic at low doses. It does not block primary afferent impulses so may precipitate an opioid abstinence syndrome. Although buprenorphine has a ceiling effect for analgesia, the dosage listed is within the ceiling effect. to the thalamus,11 and therefore is not a spinal analgesic (Fig. 1).

3 Epidural anesthesia with a local anesthetic differs in several is important for successful postsurgical outcome. Similarly, important ways from analgesia with an opioid. Epidural anes- meticulous vigilance, including constant adherence to the three thesia is often accompanied by hypotension, which is often critical principles of depth, width, and duration of analgesia, is undesirable, and by muscle relaxation, which is generally posi- mandatory if the positive preclinical findings for preemptive tive. On the other hand, hypotension is uncommon during analgesia are to be achieved in clinical practice. epidural analgesia with opioids alone. Therefore, epidural anal- gesia may be more convenient than epidural anesthesia as a References component of preemptive analgesia. The effects of opioids differ according to their receptor specificity, e.g., whether they 1. Wall PD. Pain 1988; 33:289-290. 2. Coderre TJ, et al. Pain 1993; 52:259-285. are m or k agonists. Mu opioids have many side effects, includ- 3. Woolf CJ, Chong M-S. Anesth Analg 1993; 77:362-379. ing respiratory depression; vagal stimulation, manifested as 4. Song S-O, Carr DB. Pain: Clin Updates 1999; VII(1). hypo-tension and bradycardia; gastrointestinal symptoms such 5. Crile G. Boston Med Surg J 1910; 163:893-904. as nausea, vomiting, and constipation; dysuria; and itching.19 6. Katz J, et al. Anesthesiology 1992; 77:439-446. Among these, respiratory depression and vomiting can be espe- 7. Aida S, et al. Pain 2000; 84:169-173. 8. Aida S, et al. Anesth Analg 1999; 89:711-716. cially serious in the postoperative patient. In my clinical experi- 9. Macrae WA, Davies HTO. In: Crombie IK, et al. (Eds). Epidemiology ence, eptazocine, a k-opioid available for clinical use in Japan, of Pain. Seattle: IASP Press 1999, pp 125-142. has no serious side effects. Thus, I prefer to use eptazocine for 10. Kehlet H. In: Cousins MJ, Bridenbaugh PO (Eds). Neural Blockade in epidural analgesia. I find a combination of a k-opioid and low- Clinical Anesthesia and Management of Pain, 3rd ed. Philadelphia: dose ketamine to be convenient. Benzomorphan opioids of the Lippincott, 1998, pp 129 -175. 11. Kondo E, et al. Pain 2002; 95:153-163. k family, such as eptazocine or its structural analogue pentazo- 12. Vick PG, Lamer TJ. Pain 2001; 92:311-313. cine, are described as having psychotomimetic effects.20 How- 13. Janis KM, Wright RN. Anesthesiology 1972; 56:405-406. ever, I have rarely found such effects in my clinical practice. 14. Tomemori N, et al. Acta Anaesthesiol Scand 1981; 25:355-359. The discrepancy between literature reports and my own experi- 15. South S, Smith MT. Pain: Clin Updates 2001; IX(5). ence may be attributable to differences in patient populations, 16. Michl T, et al. Pain 2001; 92:19-27. 17. Bon K, et al. Exp Brain Res 1996; 108:404-416. administration routes, dosages, and degrees of k-receptor selec- 18. Aida S, et al. Anesthesiology 2000; 92:1624-1630. tivity, as well as the possibility that eptazocine may have an 19. Aida S, et al. J Anesth 1997; 11:94-99. intrinsically low psychotomimetic liability. The practical dos- 20. Pfeiffer A, et al. Science 1986; 233:774-776. ages for preemptive analgesia are shown in Table 2. As with other mixed k-agonist/m-antagonist drugs, eptazocine should Sumihisa Aida, MD, PhD not be administered to patients who have been maintained Associate Professor chronically on a regimen of m-agonist agents such as morphine, oxycodone, or fentanyl. Doing so may precipitate an opioid Department of Anesthesiology abstinence syndrome. Saitama Medical School 38 Moro-Hongo Conclusions Moroyama Town 350-0495 Saitama Prefecture Successful preemptive analgesia in clinical practice can be complex and challenging. Careful attention is required above Japan and beyond the usual anesthetic management of circulatory Tel: 81-49-276-1271 status, respiration, fluid balance, glucocorticoid replacement, Fax: 81-49-276-1773 and so on. Careful perioperative management of all these factors Email: [email protected]

IASP was founded in 1973 as a nonprofit organization to foster and encourage research on pain mechanisms and pain syndromes, and to help improve the care of patients with acute and chronic pain. IASP brings together scientists, physicians, dentists, nurses, psychologists, physical thera- pists, and other health professionals who have an interest in pain research and treatment. Information about membership, books, meetings, etc., is available from the address below or on the IASP Web page: www.iasp-pain.org. Free copies of back issues of this newsletter are available on the IASP Web page. Timely topics in pain research and treatment have been selected for publication but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily reflect those of IASP or of the Officers or Councillors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends that there should be independent verification of diagnoses and drug dosages. For permission to reprint or translate this article, contact: International Association for the Study of Pain, 909 NE 43rd St., Suite 306, Seattle, WA 98105-6020 USA Tel: 206-547-6409; Fax: 206-547-1703; email: [email protected]; Internet: www.iasp-pain.org and www.painbooks.org Copyright © 2005, International Association for the Study of Pain®. All rights reserved. ISSN 1083-0707.

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