Techniques in Regional Anesthesia & Pain Management
Volume 11, Issue 1 , Pages 19-26 , January 2007

Recent advances in nonopioid analgesics for acute pain management

  • Asokumar Buvanendran, MD

      Affiliations

    • Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois
    • Corresponding Author InformationAddress reprint requests and correspondence: Asokumar Buvanendran, MD, Department of Anesthesiology, 1653 W. Congress Parkway, # 739, Rush University Medical Center, Chicago, IL 60612.
    • ,
  • Scott S. Reuben, MD

      Affiliations

    • Department of Anesthesiology, Baystate Medical Center and the Tufts University School of Medicine, Springfield, Massachusetts.
    • ,
  • Jeffrey S. Kroin, PhD

      Affiliations

    • Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois

References 

  1. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471–475
  2. White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg. 2005;101:S5–S22
  3. Woolf CJ. Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Res. 1981;209:491–495
  4. Mercadante S, Ferrera P, Villari P, et al. Hyperalgesia: an emerging iatrogenic syndrome. J Pain Symptom Manage. 2003;26:769–775
  5. Chia YT, Liu K, Wang JJ, et al. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth. 1999;48:872–877
  6. Larcher A, Laulin JP, Celerier E, et al. Acute tolerance associated with a single opiate administration: involvement of N-methyl-D-aspartate-dependent pain facilatory systems. Neuroscience. 1998;84:583–589
  7. Dunbar SA, Karamian I, Zhang J. Ketorolac prevents recurrent withdrawal induced hyperalgesia but does not inhibit tolerance to spinal morphine in the rat. Eur J Pain. 2007;11:1–6
  8. Raja SN, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology. 1988;68:571–590
  9. McCormack K. Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain. 1994;59:9–43
  10. Souter AJ, Fredman B, White PF. Controversies in the perioperative use of nonsteroidal anti-inflammatory drugs. Anesth Analg. 1994;79:1178–1190
  11. Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. Br J Anaesth. 1991;66:703–712
  12. Reuben SS, Connelly NR, Lurie SD, et al. Dose-response of ketorolac as an adjunct to patient-controlled analgesia morphine in patients after spinal fusion surgery. Anesth Analg. 1998;87:98–102
  13. United States Acute Pain Management Guideline Panel. Acute Pain Management: Operative or Medical Procedures and Trauma. Pub. no. 92-0032. Rockville, MD, United States Department of Health and Human Services, Public Health Service Agency for Health Care Policy and Research, 1992
  14. Ashburn MA, Caplan RA, Carr DB, et al. Practice guidelines for acute pain management in the perioperative setting (An updated report by the American Society of Anesthesiologists task force on acute pain management). Anesthesiology. 2004;100:1573–1581
  15. Muth-Selbach US, Tegeder I, Brune K, et al. Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation. Anesthesiology. 1999;91:231–239
  16. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002;99:13926–13931
  17. Hersh EV, Lally ET, Moore PA. Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray?. Curr Med Res Opin. 2005;21:1217–1226
  18. Pickering G, Loriot MA, Libert F, et al. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther. 2006;79:371–378
  19. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth. 2005;94:505–513
  20. Hyllested M, Jones S, Pedersen JL, et al. Comparative effect of paracetamol, NSAIDs, or their combination in postoperative pain management: a qualitative review. Br J Anaesth. 2002;88:199–214
  21. Sinatra R. Role of COX-2 inhibitors in the evolution of acute pain management. J Pain Symptom Manag. 2002;24:S18–S27
  22. Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen, nonsteroidal anti-inflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone?. Anesthesiology. 2005;103:1296–1304
  23. Romsing J, Moniche S. A review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for postoperative pain. Acta Anaesthesiol Scand. 2004;48:525–546
  24. Buvanendran A, Kroin JS, Tuman KJ, et al. Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor of pain management and recovery of function after knee replacement. J Am Med Assoc. 2003;290:2411–2418
  25. Reuben SS, Gutta SB, Maciolek H, et al. Effect of initiating a multimodal analgesic regimen upon patient outcomes after anterior cruciate ligament reconstruction for same-day surgery: a 1200-patient case series. Acute Pain. 2004;6:87–93
  26. Reuben SS, Gutta SB, Maciolek H, et al. Effect of initiating a preventative multimodal analgesic regimen upon long-term patient outcomes after anterior cruciate ligament reconstruction for same-day surgery: a 1200-patient case series. Acute Pain. 2005;7:65–73
  27. Battacharyya T, Smith RM. Cardiovascular risks of coxibs: The orthopaedic perspective. J Bone Joint Surg Am. 2005;87:245–246
  28. Bombardier C, Laine L, Reicin A, et al. VIGOR study group Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520–1528
  29. Mukherjee D, Topol EJ. Cox-2: where are we in 2003? Cardiovacscular risk and Cox-2 inhibitors. Arthritis Res Ther. 2003;5:8–11
  30. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary bypass surgery. J Thorac Cardiovasc Surg. 2003;125:1481–1492
  31. Nussmeier NA, Whelton AA, Brown MT, et al. Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery. Anesthesiology. 2006;104:518–526
  32. National Institutes of Health. Use of non-steroidal anti-inflammatory drugs suspended in large Alzheimer’s disease prevention trial. Bethesda, MD: NIH; 2004;
  33. Levesque LE, Brophy JM, Zhang B. The risk of myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med. 2005;142:481–489
  34. Young D. FDA labors over NSAID decisions: panel suggests COX-2 inhibitors stay available. Am J Health Syst Pharm. 2005;62:6988;6972
  35. Cochrane DJ, Jarvis B, Keating GM. Etoricoxib. Drugs. 2002;62:2637–2651
  36. Agrawal NG, Rose MJ, Matthews CZ, et al. Pharmacokinetics of etoricoxib in patients with hepatic impairment. J Clin Pharmacol. 2003;43:1136–1148
  37. Matsumoto AK, Cavanaugh PF. Etorocoxib. Drugs Today. 2004;40:395–414
  38. Leung AT, Malmstrom K, Gallacher AE, et al. Efficacy and tolerability profile of etoricoxib in patients with osteoarthritis: a randomized, double-blind, placebo and active-comparator controlled 12-week efficacy trial. Curr Med Res Opin. 2002;18:49–58
  39. Chang DJ, Chang DJ, Desjardins PJ, et al. The analgesic efficacy of etoricoxib compared with oxycodone/acetaminophen in an acute postoperative pain model: a randomized, double-blind clinical trial. Anesth Analg. 2004;99:807–815
  40. Mangold KB, Gu H, Rodriguez LC, et al. Pharmacokinetics and metabolism of lumiracoxib in healthy male subjects. Drug Metab Dispos. 2004;32:566–571
  41. Esser R, Bery C, Du Z, et al. Preclinical pharmacology of luxiracoxib: a novel selective inhibitor of cyclooxygenase-2. Br J Pharmacol. 2005;144:538–550
  42. Lehmann R, Brzosko M, Kopsa P, et al. Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double blind study vs placebo and celecoxib. Curr Med Res Opim. 2005;21:517–526
  43. Zelenakas K, Fricke JR, Jayawardene S, et al. Analgesic efficacy of single oral doses of lumiracoxib and ibuprofen in patients with postoperative dental pain. Int J Clin Pract. 2004;58:251–256
  44. Chan VW, Clark AJ, Davis JC, et al. The post-operative analgesic efficacy and tolerability of lumiracoxib compared with placebo and naproxen after total knee or hip arthroplasty. Acta Anaesthesiol Scand. 2005;49:1491–1500
  45. Schnitzer TJ, Beier J, Geusens P, et al. Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;51:549–557
  46. Salter MW. Cellular signaling pathways of signal pain neuroplasticity as targets for analgesic development. Curr Top Med Chem. 2005;5:557–567
  47. Ault B, Evans RH, Francis AA, et al. Selective depression of excitatory amino acids induced depolarizations by magnesium ions in isolated spinal cord preparations. J Physiol. 1980;307:413–428
  48. Kew JN, Kemp JA. Ionotropic and metabotrophic glutamate receptor structure and pharmacology. Psychopharmacology. 2005;179:4–29
  49. Nishimura W, Muratani T, Tatsumi S, et al. Characterization of N-methyl-D-aspartate receptor subunits responsible for postoperative pain. Eur J Pharmacol. 2004;503:71–75
  50. Burton AW, Lee DH, Saab C, et al. Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behavior in a rat model. Reg Anesth Pain Med. 1999;24:208–213
  51. McCartney CJ, Sinha A, Katz J. A qualitative systemic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg. 2004;98:1385–4000
  52. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44:293–299
  53. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systemic review. Anesth Analg. 2004;99:482–495
  54. Ong CK, Lirk P, Seymour RA, et al. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg. 2005;100:754–756
  55. Bell RF, Dahl JB, Moore RA, et al. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systemic review. Acta Anaesthesiol Scand. 2005;49:1405–1428
  56. Elia N, Tramer MR. Ketamine and postoperative pain–a quantitative systematic review of randomised trials. Pain. 2005;113:61–70
  57. Suzuki M, Haraguti S, Sugimoto , et al. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology. 2006;105:111–119
  58. De Kock M, Lavand’homme P, Waterloos H. ‘Balanced analgesia’ in the perioperative period: is there a place for ketamine?. Pain. 2001;92:373–380
  59. Wong BY, Coulter DA, Choi DW, et al. Dextrorphan and dextromethorphan, common antitussives, are antiepliptic and antagonize N-methyl-D-aspartate in brain slices. Neurosci Lett. 1988;85:261–266
  60. LePage KT, Ishmael JE, Low CM, et al. Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors. Neuropharmacology. 2005;49:1–16
  61. Duedahl TH, Dirks J, Petersen KB, et al. Intravenous dextromethorphan to human volunteers: relationship between pharmacokinetics and anti-hyperalgesic effect. Pain. 2005;113:360–368
  62. Yeh CC, Wu CT, Lee MS, et al: Analgesic effects of preincisional administration of dextromethorphan and tenoxican following laproscopic cholecystectomy. Acta Anaesthesiol Scan 48:1049-1053
  63. Weinbroum AA, Bender B, Bickels J, et al. Preoperative and postoperative dextromethorphan provides sustained reduction in postoperative pain and patient-controlled epidural analgesia requirement: a randomized, placebo-controlled, double-blind study in lower-body bone malignancy-operated patients. Cancer. 2003;97:2334–2340
  64. Wadhwa A, Clarke D, Goodchild CS, et al. Large-dose oral dextromethorphan as an adjunct to patient-controlled analgesia with morphine after knee surgery. Anesth Analg. 2001;92:448–454
  65. Duedahl TH, Romsing J, Moniche S, et al. A qualitative systemic review of peri-operative dextromethorphan in post-operative pain. Acta Anaesthesiol Scand. 2006;50:1–13
  66. Tramer MR, Schneider J, Marti R-A, et al. Role of magnesium sulfate in postoperative analgesia. Anesthesiology. 1996;84:340–347
  67. Koinig H, Wallner T, Marhofer P, et al. Magnesium sulfate reduces intra- and postoperative analgesic requirements. Anesth Analg. 1998;87:206–210
  68. Seyhan TO, Tugrul M, Sunmgur MO. Effects of three different dose regimes of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth. 2006;96:347;252
  69. Thurnau GR, Kemp DB, Jarvis A. Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate: a preliminary report. Am J Obstet Gynecol. 1987;157:1435–1438
  70. Ascher P, Nowack L. Electrophysiological studies of NMDA receptors. TINS. 1987;10:284–288
  71. Kroin JS, McCarthy RJ, Van Roenn N, et al. Magnesium sulfate potentiates morphine antinociception at the spinal level. Anesth Analg. 2000;90:913–917
  72. Buvanendran A, McCarthy RJ, Kroin JS, et al. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg. 2002;95:661–666
  73. Unnerstall , Kopejtic TA, Kahr MJ. Distribution of alpha 2 agonist binding sites in the rat and human central nervous system: analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenegic agents. Brain Res. 1984;319:69–101
  74. Yaksh TL. Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav. 1985;22:845–858
  75. Eisenach JC, Tong C. Site of hemodynamic effects of intrathecal α-2 adrenergic agonists. Anesthsiology. 1991;74:766–771
  76. Kahn ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Anaesthesia. 1999;54:146–165
  77. Duflo F, Boselli EM, Ryvlin P, et al. Spinal muscarinic and nicotinic subtypes activated by clonidine in postincisional pain. Anesthesiology. 2005;103:1253–1258
  78. Mayson KV, Gofton EA, Chambers KG. Premedication with low dose oral clonidine does not enhance postoperative analgesia of intrathecal morphine. Can J Anaesth. 2000;47:752–757
  79. Yanagidate R, Hamaya Y, Dohi S. Clonidine premedication reduces maternal requirement for intravenous morphine after cesarean delivery without affecting newborn’s outcome. Reg Anesth Pain Med. 2001;26:461–467
  80. Hidalgo MP, Auzani JA, Rumpel LC, et al. The clinical effect of small oral clonidine doses on perioperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg. 2005;100:795–802
  81. Yaksh TL. Calcium channels as therapeutic targets in neuropathic pain. J Pain. 2006;7(suppl 1):S13–S30
  82. Gee NS, Brown JP, Dissanyayake VUK. The novel anticonvulsant drug, gabapentin (neurontin), bind to the α2δ subunit of a calcium channel. J Biol Chem. 1996;271:5768–5776
  83. Kroin JS, Buvanendran A, Nagella SKS, et al. Postoperative pain and analgesic responses are similar in male and female Sprague-Dawley rats. Can J Anesth. 2003;50:904–908
  84. Field MJ, Hollomanb EF, McCleary S, et al. Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. JPET. 1997;282:1242–1246
  85. Pandey CK, Singhal V, Kumar M, et al. Gabapentin provides effective postoperative analgesia whether administered pre-emptively or post-incision. Can J Anaesth. 2005;52:827–831
  86. Radhakrishnan N, Pithal PK, Charturvedi A. Effect of preemptive gabapentin on postoperative pain relief and morphine consumption following lumbar laminectomy and disectomy: a randomized, double-blinded, placebo-controlled study. J Neurosurg Anesthesiol. 2005;17:172–173
  87. Dahl JB, Mathiesen O, Moiniche S. ‘Protective premedication’: an option with gabapentin and related drugs?. Acta Anaesthsiol Scand. 2004;48:1130–1136
  88. Menigaux C, Adam F, Guignard B, et al. Preoperative gabapentin decreases anxiety and improves early functional recovery from knee surgery. Anesth Analg. 2005;100:1394–1395
  89. Gilron I, Orr E, Tu D, et al. A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy. Pain. 2005;113:191–200
  90. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain - a systematic review of randomized controlled trials. Pain. 2006;126:91–101
  91. Hurley RW, Cohen SP, Williams KA, et al. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med. 2006;31:237–247
  92. Fassoulaki A, Stamatakis E, Petropoulos G, et al. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006;23:136–141
  93. Danshaw CB. An anesthetic approach to amputation and pain syndromes. Phys Med Rehabil Clin North Am. 2000;11:553–557
  94. Bian F, Li Z, Offord J, et al. Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. Brain Res. 2006;1075:68–80
  95. Randinitis EJ, Posvar EL, Alvey CW. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003;43:277–283
  96. Reuben SS, Buvanendran A, Kroin JS, et al. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg. 2006;103:1–6

PII: S1084-208X(07)00003-1

doi: 10.1053/j.trap.2007.02.002

Techniques in Regional Anesthesia & Pain Management
Volume 11, Issue 1 , Pages 19-26 , January 2007

Article Tools