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  • Print publication year: 2015
  • Online publication date: April 2015

Chapter 15 - Pharmacologic management of acute pain in trauma

from Section 2 - Techniques for monitoring, imaging, and pain relief


1. Taxonomy of pain syndromes. In Charlton JE, ed. Core Curriculum for Professional Education in Pain. Seattle, WA: IASP Press, 2005.
2. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150: 971–9.
3. Peden M, McGee K, Krug E, eds. Injury: a Leading Cause of the Burden of Disease, 2000. Geneva: World Health Organization, 2002.
4. Corso P, Finkelstein E, Miller T, Fiebelkorn I, Zaloshnja E. Incidence and lifetime costs of injuries in the United States. Inj Prev 2006; 12: 212–18.
5. Minei JP, Schmicker RH, Kerby JD, et al. Severe traumatic injury: regional variation in incidence and outcome. Ann Surg 2010; 252: 149–57.
6. Jennings PA, Cameron P, Bernard S. Epidemiology of prehospital pain: an opportunity for improvement. Emerg Med J 2010; 28: 530–1.
7. Guru V, Dubinsky I. The patient vs. caregiver perception of acute pain in the emergency department. J Emerg Med 2000; 18: 7–12.
8. Heins JK, Heins A, Grammas M, et al. Disparities in analgesia and opioid prescribing practices for patients with musculoskeletal pain in the emergency department. J Emerg Nurs 2006; 32: 219–24.
9. Albrecht E, Taffe P, Yersin B, et al. Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study. Br J Anaesth 2013; 110: 96–106.
10. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009; 10: 447–85.
11. Ji Y, Murphy AZ, Traub RJ. Estrogen modulation of morphine analgesia of visceral pain in female rats is supraspinally and peripherally mediated. J Pain 2007; 8: 494–502.
12. Herrero JF, Laird JM, Lopez-Garcia JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 2000; 61: 169–203.
13. Nakai A, Kumakura Y, Boivin M, et al. Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using alpha-[11C]methyl-L-tryptophan, positron emission tomography and statistical parametric mapping. Can J Gastroenterol 2003; 17: 191–6.
14. Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007; 28: 521–74.
15. Bereiter DA, Cioffi JL, Bereiter DF. Oestrogen receptor-immunoreactive neurons in the trigeminal sensory system of male and cycling female rats. Arch Oral Biol 2005; 50: 971–9.
16. Silka PA, Roth MM, Moreno G, Merrill L, Geiderman JM. Pain scores improve analgesic administration patterns for trauma patients in the emergency department. Acad Emerg Med 2004; 11: 264–70.
17. Kelly AM. A process approach to improving pain management in the emergency department: development and evaluation. J Accid Emerg Med 2000; 17: 185–7.
18. AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc 2002; 50 (6 Suppl): S205–24.
19. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Phys 2005; 71: 913–18.
20. Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the antipyretic activity of paracetamol (4-acetamidophenol). Nature 1972; 240: 410–11.
21. Chandrasekharan NV, Dai H, Roos KLT, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure and expression. Proc Natl Acad Sci USA 2002; 99: 13926–31.
22. Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. J Pharmacol Exp Ther 2005; 315: 1–7.
23. Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of acetaminophen: role of cyclo-oxygenase. FASEB J 2005; 19: 635–7.
24. Herrero JF, Headly PM. Reversal by naloxone of the spinal antinociceptive actions of a systemically administered NSAIDs. Br J Pharmacol 1996; 118: 968–72.
25. Sandrini M, Romualdi P, Vitale G et al. The effect of a paracetamol and morphine combination on dynorphin A levels in the rat brain. Biochem Pharmacol 2001; 61: 1409–16.
26. Bujalska M. Effect of non-selective and selective opioid receptor antagonists on antinociception action of acetaminophen. Pol J Pharma 2004; 56: 539–45.
27. Di Marzo V, Deutsch DG. Biochemistry of the endogenous ligands of cannabinoid receptors. Neurobiol Dis 1998; 5: 386–404.
28. Bertollini A, Ferrari A, Ottani A, et al. Paracetamol: new vistas of an old drug. CNS Drug Rev 2006; 12: 250–75.
29. Mallet C. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain 2008; 139: 190–200.
30. Mallet C. TRPV1 in brain is involved in acetaminophen-induced antinociception. PLoS ONE 2010; 5: 127–48.
31. Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician 2009; 12: 269–80.
32. Barden J, Edwards J, Moore A, et al. Single dose oral paracetamol (acetaminophen) for postoperative pain (Cochrane review). Cochrane Database Syst Rev 2004; (1): CD004602.
33. McNicol ED, Tzortzopoulou A, Cepeda MS, et al. Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis. Br J Anaesth 2011; 106: 764–75.
34. Moller PL, Sindet-Pedersen S, Petersen CT, et al. Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery. Br J Anaesth 2005; 94: 642–8.
35. Anderson BJ, Pons G, Autret-Leca E, Allegaert K, Boccard E. Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis. Paediatr Anaesth 2005; 15: 282–92.
36. Juhl GI, Norholt SE, Tonnesen E, et al. Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2 g starting dose following third moral surgery. Eur J Pain 2006; 10: 371–7.
37. Ofirmev [package insert]. San Diego, CA: Cadence Pharmaceuticals, 2010.
38. Pasero C, Stannard D. The role of intravenous acetaminophen in acute pain management: a case-illustrated review. Pain Manag Nurs 2012; 13: 107–24.
39. Shaikh N, Kettern MA, Ali Ahmed AH, Louon A. Morphine sparing effect of proparacetamol in surgical and trauma intensive care. Middle East J Emerg Med 2006; 6 (2): 28–30.
40. Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy 1991; 11: 364–9.
41. Hahn TW, Mogensen T, Lund C, et al. Analgesic effect of IV paracetamol; possible ceiling effect of paracetamol in postoperative pain. Acta Anaesthesiol Scand 2003; 47: 138–45.
42. Vitols S. Paracetamol hepatotoxicity at therapeutic doses. J Intern Med 2003; 253: 95–8.
43. Bacon TH, Hole JG, North M, Burnett I. Analgesic efficacy of sustained release paracetamol in patients with osteoarthritis of the knee. Br J Clin Pharmacol 2002; 53: 629–36.
44. Cormack CRH, Sudan S, Anderson R, et al. The pharmacokinetics of a single rectal dose of paracetamol (40 mg/kg) in children with liver disease. Paediatr Anaesth 2006; 16: 417–23.
45. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 102: 822–31.
46. Dal Pan GJ. Acetaminophen: Background and Overview. Silver Spring, MD: US Food and Drug Administration, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research; 2009. (accessed July 2014).
47. Woodcock J. A difficult balance: pain management, drug safety, and the FDA. N Engl J Med 2009; 361: 2105–7.
48. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002; 22: 145–55.
49. Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010; 77: 19–27.
50. Moore PK, Marshall M. Nitric oxide releasing acetaminophen (nitroactaminophen). Dig Liver Dis 2003; 35 (Suppl 2): S49–60.
51. Anderson BJ, Palmer GM. Recent developments in the pharmacological management of pain in children. Curr Opin Anaesthesiol 2006; 19: 285–92.
52. Yeh YC, Reddy P. Clinical and economic evidence for intravenous acetaminophen. Pharmacotherapy 2012; 32: 559–79.
53. Vane JR. The fight against rheumatism: from willow bark to COX-1 sparing drugs. J Physiol Pharmacol 2000; 51: 573–86.
54. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 43: 232–5.
55. Watson DJ, Harper SE, Zhao PL, et al. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofexoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000; 160: 2998–3003.
56. Sinatra R. Role of COX-2 inhibitors in the evolution of acute pain management. J Pain Symptom Manage 2002; 24: S18–27.
57. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1 beta-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001; 410: 471–5.
58. Buvanendran A, Kroin JS, Tuman KJ, et al. Cerebrospinal fluid and plasma pharmacokintetics of the cycloxygenase 2 inhibitor rofecoxib in humans: single and multiple oral drug administration. Anesth Analg 2005; 100: 1320–4.
59. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954–9.
60. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004; 109: 2068–73.
61. Chen YF, Jobanputra P, Barton P, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess 2008; 12: 1–278.
62. W Ye, H Zhang, E Hillas, et al. Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure. Am J Renal Physiol 2006; 290: F542–9.
63. Hawkey CJ, Glitton X, Hoexter G, Richard D, Weinstein WM. Gastrointestinal tolerability of lumiracoxib in patients with osteoarthritis and rheumatoid arthritis. Clin Gastroenterol Hepatol 2006; 4: 57–66.
64. Mehallo CJ, Drezner JA, Bytomski JR. Practical management: nonsteroidal antiinflammatory drug (NSAID) use in athletic injuries. Clin J Sport Med 2006; 16: 170–4.
65. Zhang J, Diang EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events. JAMA 2006; 296: 1619–32.
66. Bannwarth B. Is licofelone, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, a promising alternative in anti-inflammatory therapy? Fundam Clin Pharmacol 2004; 18: 125–30.
67. Rahme E, Barkun AN, Toubouti Y, et al. Do proton-pump inhibitors confer additional gastrointestinal protection in patients given celecoxib? Arthritis Rheum 2007; 57: 748–55.
68. Chan F, Wong V, Suen B, et al. Combination of a cyclooxygensase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomized trial. Lancet 2007; 369: 1621–6.
69. Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective-1997, Arthritis, Rheumatism and Aging Medical Information System. J Rheumatol Suppl 1998; 51: 8–16.
70. Chen JY, Wu GJ, Mok MS, et al. Effect of adding ketorolac to intravenous morphine patient-controlled analgesia on bowel function in colorectal surgery patients: a prospective, randomized, double-blind study. Acta Anaesthesiol Scand 2005; 49: 546–51.
71. Stephens JM, Pashos CL, Haider S, Wong JM. Making progress in the management of postoperative pain: a review of the cyclooxygenase-2 specific inhibitors. Pharmacotherapy 2004; 24: 1714–31.
72. Sinha VR, Kumar RV, Singh G. Ketorolac tromethamine formulations: an overview. Expert Opin Drug Deliv 2009; 6: 961–75.
73. Predel HG, Koll R, Pabst H, et al. Diclofenac patch for topical treatment of acute impact injuries: a randomized, double blind, placebo controlled, multicentre study. Br J Sports Med 2004; 38: 318–23.
74. Spaulding J, Li F. Naproxcinod: FDA efficacy and safety review. May 12, 2010. (accessed September 2014).
75. Dimar JR, Ante WA, Zhang YP, Glassman SD. The effects of nonsteroidal anti-inflammatory drugs on posterior spinal fusion in rat. Spine 1996; 21: 1870–6.
76. Radi ZA, Khan NK. Effect of cyclooxygenase inhibition on bone, tendon and ligament healing. Inflamm Res 2005; 54: 358–66.
77. Cohen DB, Kawarmura S, Ehteshami JR, Rodeo SA. Indo-methacin and celecoxib impair rotator cuff tendon-to-bone healing. Am J Sports Med 2006; 34: 362–9.
78. Williams LJ, Pasco JA, Henry MJ, et al. Paracetamol (acetaminophen) use, fracture and bone mineral density. Bone 2011; 48: 1277–81.
79. Vestergaard P, Hermann P, Jensen JE, Eiken P, Mosekilde L. Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). Osteoporos Int 2012; 23: 1255–65.
80. Tam J, Trembovler V, Di Marzo V, et al. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J 2008; 22: 285–94.
81. Ofek O, Karsak M, Leclerc N, et al. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci USA 2006; 103: 696–701.
82. Tam J, Ofek O, Fride E, et al. Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol 2006; 70: 786–92.
83. Yaksh TL. Pharmacology and mechanisms of opioid analgesic activity. Acta Anaesthesiol Scand 1997; 41 (1pt 2): 94–111.
84. Mackersie RC, Karagianes TG, Hoyt DB, Davis JW. Prospective evaluation of epidural and intravenous administration of fentanyl for pain control and restoration of ventilatory function following multiple rib fractures. J Trauma 1991; 31: 443–9.
85. Evans E, Turley N, Robinson N, Clancy M. Randomized controlled trial of patient controlled analgesia compared with nurse delivered analgesia in an emergency department. Emerg Med J 2005; 22: 25–9.
86. George MJ. The site of action of epidurally administered opioids and its relevance to postoperative pain management. Anaesthesia 2006; 61 (7): 659–64.
87. Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand 2002; 46: 759–70.
88. Mercadante S, Villari P, Ferrera P, et al. Transmucosal fentanyl vs. intravenous morphine in doses proportional to basal opioid regimen for episodic breakthrough pain. Br J Cancer 2007; 96: 1828–33.
89. Simpson DM, Xie F, Messina J. Fentanyl buccal tablet (FBT) in the treatment of breakthrough pain in opioid tolerant patients with chronic neuropathic pain: randomized, placebo controlled study. Eur J Pain 2007; 11: 84.
90. Viscusi ER, Reynolds L, Chung F, Atkinson LE, Khanna S. Patient-controlled transdermal fentanyl hydrochloride vs. intravenous morphine pump for postoperative pain. JAMA 2004; 291: 1333–41.
91. Farr SJ, Otulana BA. Pulmonary delivery of opioids as pain therapeutics. Adv Drug Deliv Rev 2006; 58: 1076–88.
92. Rosseland L, Solheim N, Stubhaug A. Intra-articular morphine in acute pain trials. Reg Anesth Pain Med 2007; 32: 176–7.
93. Kotwal RS, O’Connor KC, Johnson TR, et al. A novel pain management strategy for combat casualty care Ann Emerg Med 2004; 44: 121–7.
94. Fulda GJ, Giberson F, Fagraeus L, Angood PB, Gentilello LM. A prospective randomized trial of nebulized morphine compared with patient-controlled analgesia morphine in the management of acute thoracic pain. J Trauma 2005; 59: 383–90.
95. Higgins MJ, Asbury AJ, Brodie MJ. Inhaled nebulised fentanyl for postoperative analgesia. Anaesthesia 1991; 46: 973–6.
96. Worsley MH, MacLeod AD, Brodie MJ, Asbury AJ, Clark C. Inhaled fentanyl as a method of analgesia. Anaesthesia 1990; 45: 449–51.
97. Macleod DB, Habib AS, Ikeda K, et al. Inhaled fentanyl aerosol in healthy volunteers: pharmacokinetics and pharmacodynamics. Anesth Analg 2012; 115: 1071–7.
98. Sinatra R. The fentanyl HCl patient-controlled transdermal system (PCTS): an alternative to intravenous patient-controlled analgesia in the postoperative setting. Clin Pharmacokinet 2005; 44 (Suppl 1): 1–6.
99. Allan L, Richarz U, Simpson K, et al. Transdermal fentanyl versus sustained release oral morphine in strong-opioid naive patients with chronic low back pain. Spine (Phila Pa 1976) 2005; 30: 2484–90.
100. Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 2009; 13: 219–30.
101. Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 1993; 339: 182–9.
102. Stein C, Millan MJ, Shippenberg TS, Peter K, Hertz A. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 1989; 248: 1269–75.
103. Stein C, Comisel K, Haimeri E, et al. Analgesic effects of intraarticular morphine after arthroscopic knee surgery. N Engl J Med 1991; 325: 1123–6.
104. Busch CA, Shore BJ, Bhandari R, et al. Efficacy of periarticular multimodal drug injection in total knee arthroplasty. J Bone Joint Surg 2006; 88: 959–63.
105. Ahlbeck K. Opioids: a two-faced Janus. Curr Med Res Opin 2011; 27: 439–48.
106. Ogilvie H. Large-intestine colic due to sympathetic deprivation: a new clinical syndrome. Br Med J 1948; 2: 671–3.
107. Rogers M, Cerda JJ. The narcotic bowel syndrome. J Clin Gastroenterol 1989; 11: 132–5.
108. Brill S, McCartney CJL, Weksler N, Chan VWS. Acute colonic pseudo-obstruction (Ogilvie’s syndrome), lower limb arthroplasty and opioids. Acute Pain 2003; 5: 45–50.
109. Weinger MB. Dangers of postoperative opioids. APSF Newslett 2006–2007; 21 (4): 61–8.
110. Roy S, Want J, Kelschenbach, Koodie L, Martin J. Modulation of immune function by morphine: implications for susceptibility to infection. J Neuroimmune Pharmacol 2006; 1: 77–89.
111. Savage S. Assessment for addiction in pain-treatment settings. Clin J Pain. 2002; 18: S28–38.
112. Illgen RL, Pellino TA, Gordon DB, Butts S, Heiner JP. Prospective analysis of a novel long-acting oral opioid analgesic regimen for pain control after total hip and knee arthroplasty. J Arthroplasty 2006; 21: 814–20.
113. Shirk MB, Donahue KR, Shirvani J. Unlabeled uses of nebulized medications. Am J Health Syst Pharm 2006; 63: 1704–16.
114. Hutchinson MR, Zhang Y, Shridhar M, et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun 2010; 24: 83–95.
115. Bamigbade TA, Langford RM. The clinical use of tramadol hydrochloride. Pain Rev 1998; 5: 155–82.
116. Gardner JS, Blough D, Drinkard CR, et al. Tramadol and seizures: a surveillance study in a managed car population. Pharmacotherapy 2000; 20: 1423–31.
117. Akinci S, Saricaoglu F, Atay O, Doral M, Kanbak M. Analgesic effect of intra-articular tramadol compared with morphine after arthroscopic knee surgery. Arthroscopy 2005; 21: 1060–5.
118. Langlois G, Estebe JP, Gentili ME, et al. The addition of tramadol to lidocaine does not reduce tourniquet and postoperative pain during IV regional anesthesia. Can J Anaesth 2002; 49: 165–8.
119. Altunkaya H, Ozer Y, Kargi E, Babuccu O. Comparison of local anaesthetic effects of tramadol with prilocaine for minor surgical procedures. Br J Anaesth 2003; 90: 320–2.
120. Pang WW, Mok MS, Chang DP, et al. Local anesthetic effects of tramadol, metaclopromide and lidocaine following intradermal injection. Reg Anesth Pain Med 1998; 23: 580–3.
121. Turker G, Goren S, Bayram S, Sahin S, Korfali G. Comparison of lumbar epidural tramadol and lumbar epidural morphine for pain relief after throracotomy: a repeated dose study. J Cardiothorac Vasc Anesth 2005; 19: 468–74.
122. Erlich DR, Bodine W. Tapentadol (nucynta) for treatment of pain. Am Fam Physician 2012; 85: 910–11.
123. Daniels S, Casson E, Stegmann JU, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin 2009; 25: 1551–61.
124. Etropolski M, Kelly K, Okamoto A, Rauschkolb C. Comparable efficacy and superior gastrointestinal tolerability (nausea, vomiting, constipation) of tapentadol compared with oxycodone hydrochloride. Adv Ther 2011; 28: 401–17.
125. Kissin I, Bright CA, Bradley EL. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine–opioid analgesic combinations? Anesth Analg 2000; 91: 1483–8.
126. Willman EV. Andolfatto G. A prospective evaluation of “ketofol” (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007; 49: 23–30.
127. Jennings PA, Cameron P, Bernard S. Ketamine as an analgesic in the pre-hospital setting: a systematic review. Acta Anaesthesiol Scand 2011; 55: 638–43.
128. Berti M, Baciarello M, Troglio R, Fanelli G. Clinical uses of low-dose ketamine in patients undergoing surgery. Curr Drug Targets 2009; 10: 707–15.
129. McGuinness SK, Wasiak J, Cleland H, et al. A systematic review of ketamine as an analgesic agent in adult burn injuries. Pain Med 2011; 12: 1551–8.
130. Koppert W, Weigand M, Neumann F, et al. Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth Analg 2004; 98: 1050–5.
131. Conlay L. Analgesic effects of intravenous lidocaine and morphine on post amputation pain: a randomized double blind, active placebo controlled, crossover trial. Surv Anesthesiol 2004; 48 (1): 43.
132. Tanaka T, Okano S, Tsukui R, et al. Continuous low dose intravenous lidocaine is effective for visceral pain secondary to peritoneal carcinomatosis in terminally cancer patients. ASCO Annual Meeting Proceedings Part 1. J Clin Oncol 2006; 24: 8533.
133. Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetics to relieve neuropathic pain: a systemic review and metanalysis. Anesth Analg 2005; 101: 1738–49.
134. Finnerup N, Biering-Sorensen F, Johannesen I, et al. Intravenous lidocaine relieves spinal cord injury pain: a randomized controlled trial. Anesthesiology 2005; 102: 1023–30.
135. Kaba A, Laurent SR, Detroz BJ, et al. Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy. Anesthesiology 2007; 106: 11–18.
136. Palmeri TL, Greenhalgh DG. Topical treatment of pediatric patients with burns: a practical guide. Am J Clin Derm 2002; 3: 529–34.
137. Spierings ELH, Brevard JA, Katz NP. Two-minute skin anesthesia through ultrasound pretreatment and iontophoretic delivery of a topical anesthetic: a feasibility study. Pain Med 2008; 9: 55–9.
138. Mofenson HC, Caraccio TR, Miller H, Greensher J. Lidocaine toxicity from topical mucosal application. Clin Pediatr 1983; 22: 190–2.
139. Dasta J, Ramamoorthy S, Patou G, Sinatra R Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting. Curr Med Res Opin 2012; 28: 1609–15.
140. Hu D, Onel E, Singla N, Kramer WG, Hadzic A. Pharmacokinetic profile of liposome bupivacaine injection following a single administration at the surgical site. Clin Drug Investig 2013; 33: 109–15.
141. Paneral AE, Monza G, Movilia P, Francucci BM, Tiengo M. A randomized within-patient crossover placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortryptyline in central pain. Acta Neurol Scand 1990; 82: 34–8.
142. Carter GT, Sullivan MD. Antidepressants in pain management. Curr Opin Investig Drugs 2002; 3: 454–8.
143. Vieweg WVR, Weed MA. Tricyclic antidepressants, QT interval prolongation and torsade de pointes. Psychosomatics 2004; 45: 371–7.
144. Ray W, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharm Ther 2004; 75: 234–41.
145. Cappell MS. Colonic toxicity of administered drugs and chemicals. Am J Gastroenterol 2004; 99: 1175–90.
146. Hayes JR, Bojral S, McCarthy MC. Gastrointestinal effects of tricyclic antidepressants: Ogilvie’s syndrome. Psychosomatics 1987; 28: 442–3.
147. Attal N, Cruccu G, Haanpaa M et al. EFNS guidelines in pharmacological treatment of neuropathic pain. Eur J Neurol 2006; 13: 1153–69.
148. Orii R, Obashi Y, Haldar S, et al. GABAergic interneurons at supraspinal and spinal levels differentially modulate the antinociceptive effects of nitrous oxide in Fischer rats. Anesthesiology 2003; 98: 1223–30.
149. Gottrup H, Juhl G, Kristensen AD, et al. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 2004; 101: 1400–8.
150. Sihoe AD, Lee TW, Wan IY, Thung KH, Yim AP. The use of gabapentin for post-operative and post-traumatic pain in thoracic surgery patients. Eur J Cardiothorac Surg 2006; 29: 795–9.
151. Coderre TJ, Kumar N, Lefebvre CD, Yu JS. Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate. J Neurochem 2005; 94: 1131–9.
152. Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: Meta-analysis. Can J Anaesth 2006; 53: 461–9.
153. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin or their combination for neuropathic pain. N Engl J Med 2005; 352: 1324–34.
154. Gilron I. The role of anticonvulsant drugs in postoperative pain management: A bench to bedside perspective. Can J Anaesth 2006; 53: 562–71.
155. Dahl JB, Mathiesen O, Moiniche S. “Protective premedication”: an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anaesthesiol Scand 2004; 48: 1130–6.
156. Pandey A, Feltner D, Jefferson J, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorders: a placebo-controlled, multicenter study. J Clin Psychopharmacol 2004; 24: 141–9.
157. Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol 2004; 3: 618–21.
158. MacPherson RD. The pharmacological basis of contemporary pain management. Pharmcol Therapeut 2000; 88: 163–85.
159. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Anaesthesia 1999; 54: 146–65.
160. Vulliemoz Y, Virag L, Whittington RA. Interaction of alpha-2-adrenergic and opioid receptor with the cGMP system in the mouse cerebellum. Brain Res 1998; 813: 26–31.
161. Xu Z, Li P, Tong C, et al. Location and characteristics of nitric oxide synthetase in sheep spinal cord and its interaction with alpha(2)-adrenergic and cholinergic anti-nociception. Anesthesiology 1996; 84: 890–9.
162. Bernard JM, Hommeril JL, Passuti N, Pinaud M. Postoperative analgesia by intravenous clonidine. Anesthesiology 1991; 75: 577–82.
163. Daqing M, Rajakumaraswamy N, Maze M. α2-Adrenoceptor agonists: shedding light on neuroprotection? Br Med Bull 2005; 71: 77–92.
164. Virtanen R, Savola JM, Sano V, Nyman L. Characterization of selectivity, specificity and potency of medetomidine as alpha-2 adrenoreceptor agonist. Eur J Pharmacol 1988; 150: 9–14.
165. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg 2004; 98: 153–8.
166. Talon MD, Woodson LC, Sherwood E, Aarsland A, McRae L. Nasal dexmedetomdine is comparable to midazolam as preoperative sedative in children. Anesthesiology 2007; 107: A1398.
167. Devabhakthuni S, Pajoumand M, Williams C, et al. Evaluation of dexmedetomidine: safety and clinical outcomes in critically ill trauma patients. J Trauma 2011; 71: 1164–71.
168. Lyons FM, Bew S, Sheeran P, Hall GM. Effects of clonidine on pituitary hormonal response to pelvic surgery. Br J Anaesth 1997; 78: 134–7.
169. Mukhtar AM, Obayah EM, Hassona AM. The use of dexmedetomidine in pediatric cardiac surgery. Anesth Analg 2006; 103: 52–6.
170. Patterson DR, Ptacek JT, Carrougher GJ, Sharar SR. Lorezepam as an adjunct to opioid analgesics in the treatment of burn pain. Pain 1997; 72: 367–74.
171. Kaabachi O, Ouezini R, Koubaa W, Ghrab B. Comparative study between mask nebulization and oral administration of midazolam in children. Anesthesiology 2007; 107: A1095.
172. Scott R. Buccal midazolam as rescue therapy for acute seizures. Lancet Neurol 2005; 4: 592–3.
173. Harbord MG, Kyrkou NE, Kay D, Coulthard KP. Use of intranasal midazolam to treat acute seizures in paediatric community settings. J Paediatr Child Health 2004; 40: 556–8.
174. Whiting PJ. GABA-A receptor subtype in the brain: a paradigm for CNS drug delivery. Drug Discov Today 2003; 8: 445–50.
175. Yaksh TL, Allen JW. The use of intrathecal midazolam in humans: a case study process. Anesth Analg 2004; 98: 1536–45.
176. Goh PL, Lee SW, Goh SH. Analgesia for adult distal radius fracture manipulation in the emergency department: demand valve nitrous oxide compared with intravenous regional anaesthesia. Hong Kong J Emerg Med 2002; 9: 181–7.
177. Wilson MJ, Hunter JB. Supracondylar fractures of the humerus in children-wire removal in the outpatient setting. Injury Extra 2006; 37: 313–15.
178. Burm AGL. Occupational hazards of inhalational anaesthetics. Best Pract Res Clin Anaesthesiol 2003; 17: 147–61.
179. Buntine P, Thom O, Babl F, Bailey M, Bernard S. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas 2007; 19: 509–14.
180. Babl FE, Jamison SR, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas 2006; 18: 404–10.
181. Wasiak J, Mahar PD, Paul E, et al. Inhaled methoxyflurane for pain and anxiety relief during burn wound care procedures: an Australian case series. Int Wound J 2014; 11: 74–8.
182. Grindlay J, Babl FE. Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas 2009; 21: 4–11.
183. Ziegler AW, Agarwal NN. Morbidity and mortality of rib fractures. J Trauma 1994; 37: 975–9.
184. Bergeron E, Lavoie A, Clas D, et al. Elderly trauma patients with rib fractures are at a greater risk of death and pneumonia. J Trauma 2002; 54: 478–85.
185. Schneider JC, Harris NL, El Shami A, et al. A descriptive review of neuropathic-like pain after burn injury. J Burn Care Res 2006; 27: 524–8.
186. Jellish WS, Gamelli RL, Furry PA, McGill VL, Fluder EM. Effect of topical local anesthetic application to skin harvest sites for pain management in burn patients undergoing skin-grafting procedures. Ann Surg 1999; 229: 115–20.
187. Wehner D, Hamilton GC. Seizures following application of local anesthetics to burn patients. Ann Emerg Med 1984; 13: 456–8.
188. Rincon E, Bakern RL, Iglesias AJ, Duarte AM. CNS toxicity after topical application of EMLA cream with molluscum contagiosum. Pediatr Emerg 2000; 16: 252–4.
189. Hahn IH, Hoffman RS, Nelson LS. EMLA induced methemogobinemia and systemic topical anesthetic toxicity. J Emerg Med 2004; 26: 85–8.
190. Heinrich M, Wetzstein V, Muensterer OJ, Till H. Conscious sedation: Off label use of rectal S(+) ketamine and midazolam for wound dressing changes in paediatric heat injuries. Eur J Pediatr Surg 2004; 14: 235–9.
191. Summer G, Puntillo K, Miaskowski C, Green P, Levine J. Burn injury pain: the continuing challenge. J Pain 2007; 8: 533–48.
192. Baker RA, Zeller RA, Klein RL, et al. Burn wound itch control using H1 and H2 antagonists. J Burn Care Rehabil 2001; 22: 263–8.
193. Mendham JE. Gabapentin for the treatment of itching produced by burns and wound healing in children: a pilot study. Burns 2004; 30: 851–3.
194. Galinski M, Picco N, Hennequin B, et al. Out-of-hospital emergency medicine in pediatric patients: prevalence and management of pain. Am J Emerg Med 2011; 29: 1062–6.
195. Jacob E, Puntillo KA. Variabiltiy of analgesic practices for hospitalized children on different pediatric speciality units. J Pain Symptom Manage 2000; 20: 59–67.
196. Cohen SP, Christo PJ, Moroz L. Pain management in trauma patients. Am J Phys Med Rehabil 2004; 83: 142–61.
197. Clark E, Plint AC, Correll R, Gaboury I, Passi B. A randomized controlled trial of acetaminophen, ibuprofen and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics 2007; 119: 460–7.
198. Falanga IJ, Lafrenaye S, Mayer SK, Tetrault JP. Management of acute pain in children: safety and efficacy of a nurse-controlled algorithm for pain relief. Acute Pain 2006; 8: 45–54.
199. Patterson DR, Hoffman HG, Weichman SA, Jensen MP, Sharar SR. Optimizing control of pain from severe burns: a literature review. Am J Clin Hypn 2004; 47: 43–54.
200. Lang T, Barker R, Steinlechner B, et al. TENS relieves acute posttraumatic hip pain during emergency transport. J Trauma 2007; 62: 184–8.
201. McMakin CR, Gregory WM, Phillips TM. Cytokine changes with microcurrent treatment of fibromyalgias associated with cervical spine trauma. J Bodywork Move Ther 2005; 9: 169–76.
202. Ducharme J. Emergency pain management: a Canadian Association of Emergency Physicians (CAEP) consensus document. J Emerg Med 1994; 12: 855–66.