Inadequate pain management is believed to result in adverse outcomes such as activation of stress responses, cardiovascular, respiratory and gastrointestinal effects. Studies indicate that use of analgesic techniques such as PCA and epidural administration of morphine provide more effective pain relief and improved patient satisfaction compared with intramuscular (i.m.) morphine bolus injections administered by hospital staff on a PRN basis [28,29]. In addition to increased patient comfort and pain relief, improved analgesic techniques have other benefits. Data indicate that use of PCA leads to earlier patient mobilization and, consequently, to reduced hospital stay and costs [30,31].
However, as noted above, patients can experience discomfort and side-effects postoperatively as a result of their analgesic medication, e.g. opioid-related side-effects are common in postsurgical patients . Thus, multimodal therapeutic strategies employing new analgesic techniques such as PCA morphine with non-opioid analgesics to reduce opioid consumption are increasingly applied in the improvement of patient comfort and mobilization and to reduce drug-related side-effects [32-35]. Within this context, there is great scope for new analgesic agents that provide good efficacy combined with improved safety profiles compared with currently available agents such as traditional anti-inflammatory drugs.
In 1995, a list of potentially novel therapeutic approaches for treating pain and inflammation was proposed . This was based on research at that time into molecules involved in peripheral and central pain-signalling pathways that could be targeted as potential areas of analgesic intervention. Bradykinin contributes to inflammation and pain by activation and sensitization of primary afferent nociceptors through B1 and B2 receptors . Research demonstrated that B1 and B2 receptor antagonists could attenuate hyperalgesia in animal models [37-40]. Therefore, it was hypothesized that the development of non-peptide receptor-antagonists could provide useful analgesic/anti-inflammatory agents.
In addition to peripherally acting agents, analgesic/anti-inflammatory agents that target the CNS were also proposed. Neuropeptides such as substance-P, neurokinin A and B, etc., are important neurotransmitters in the pain pathway . Substance-P and neurokinin A (NKA) are released in the CNS in response to noxious peripheral stimulation and activate secondary afferent neurons in the spinal cord by binding to their receptors, NK-1 and NK-2, respectively [48-51]. Peptide antagonists for NK-1 and NK-2 have been known for several years . However, the development of non-peptide antagonists for these receptors, which were demonstrated to be antinociceptive in various animal models for hyperalgesia, provided a new breakthrough .
Epibatidine, a compound isolated from the skin of an Ecuadorian frog, showed antinociceptive activity in rodents with a potency that was 100 times that of therapeutic morphine doses in standard animal pain models . However, although this is an extremely potent analgesic, doses only a little above the proposed therapeutic levels produced motor-neurone disturbances and autonomic effects . Thus, there was a seemingly broad spectrum of potential therapeutic targets for developing new analgesic and anti-inflammatory agents. However, despite wide possibilities, in recent years only COX-2-selective inhibition has emerged successfully from research and development, clinical development, and clinical trials to become available as new, effective and safe anti-inflammatory drugs on the market.
The mechanism of action of NSAIDs is related to the inhibition of cyclo-oxygenase, an enzyme that converts arachidonate to a variety of prostanoids including prostaglandins and thromboxane [12,55]. There are two known isoforms of cyclo-oxygenase, COX-1 and COX-2 . COX-1 is constitutively expressed in most tissues and plays an important role in platelet function and in the protection of the gastric mucosa. COX-2 expression is low or undetectable in most tissues . However, expression of COX-2 can be induced in most cell types, including sites of inflammation in response to proinflammatory stimuli such as IL-1β and TNFα [58-61].
Upregulation of COX-2 expression in response to inflammatory stimuli leads to an increase in prostaglandins that mediate inflammation, pain and fever [55,62]. In addition to increased expression in peripheral inflammatory sites, COX-2 expression is induced in sensory neurons in the CNS in response to inflammatory stimuli [11,41,63,64]. Thus, COX-2 has both a peripheral and central role in inflammatory pain mechanisms (Fig. 4)[63,64]. COX-2-selective inhibitors need to provide analgesic and anti-inflammatory efficacy at least equivalent to conventional NSAIDs, while providing a significantly improved safety and tolerability profile. In particular, COX-2-selective inhibitors should not inhibit COX-1-mediated platelet function or cause serious gastrointestinal complications such as upper gastrointestinal tract ulceration, perforation and bleeding associated with inhibition of COX-1 in the gastric mucosa.
A direct correlation between the inhibition of COX-2 activity and the reduction in inflammation has been demonstrated in vivo[9,41,42,65,66]. In rats injected with carageenan directly into the pad of the foot, celecoxib, a selective COX-2 inhibitor, reduced both oedema (the footpad volume) and hyperalgesia (the change in withdrawal latency) as a measure of pain response . In contrast, no reduction in oedema or hyperalgesia was observed in response to a highly selective COX-1 inhibitor, SC-560, compared with placebo (Fig. 5a). Direct injection of NSAIDs into the spinal cord has been shown to inhibit hyperalgesic responses, and increased concentrations of COX-2 mRNA and prostaglandins in the spinal cord have been observed in response to peripheral stimulation [41,65-67]. PGE2 concentrations in the cerebrospinal fluid (CSF) increase dramatically following injection of carageenan into the rat footpad [41,65,66]. Administration of celecoxib in this animal model resulted in almost a 100% reduction in PGE2 levels in the CSF, whereas SC-560 had no significant effect on PGE2 levels even at pharmacologically effective concentrations (Fig. 5b).
Despite our best efforts, current treatment strategies for the management of acute pain often fall short and pain is often undertreated. New approaches to pain management including improved education and training of healthcare providers, new therapeutic strategies, and novel analgesic and anti-inflammatory agents all contribute to the improved management of acute pain, including postsurgical pain. Novel analgesics that provide good efficacy with an improved safety profile compared with currently available treatment options are essential components for the achievement of this goal. Increased COX-2 expression and the consequent production of high concentrations of prostaglandins in inflamed tissue and in the central nervous system are key mediators in inflammatory pain. COX-2 inhibition reduces prostaglandin concentrations and inhibits inflammation and hyperalgesia. Conventional NSAIDs are potent inhibitors of COX-2. However, at therapeutic doses, these agents also inhibit COX-1, a constitutively expressed enzyme that plays an important homeostatic role in platelets and in the gastric mucosa. Inhibition of COX-1 leads to inhibition of platelet aggregation and potential bleeding complications, and to gastroduodenal ulceration, perforation and bleeding that can be potentially life-threatening. In recent years, the development of COX-2-selective inhibitors, which inhibit COX-2 but not COX-1 at therapeutic doses, has provided new advances in the management of acute pain. COX-2-selective inhibitors provide efficacy equivalent to conventional NSAIDs, without causing serious platelet and gastrointestinal side-effects. Thus, COX-2-selective inhibitors provide an alternative therapeutic option with an improved safety profile in the management of inflammation and pain.
1. World Health Organization. Cancer Pain and Palliative Care.
Report of a WHO Expert Committee. Technical Report Series No. 84. Geneva, Switzerland: WHO, 1990.
2. Fishman S, Borsook D. Opioids in pain management. In: Benzon H, Raja S, Molloy RE, Strichartz G, eds. Essentials of Pain Medicine and Regional Anesthesia.
New York, USA: Churchill Livingstone, 1999: 51-54.
3. Zuckerman L, Ferrante F. Nonopioid and opioid analgesics. In: Ashburn M, Rice L, eds. The Management of Pain.
Philadelphia, USA. Churchill Livingstone, 1998: 111-140.
4. Wong H, Benzon H. Epidural opioid analgesia. In: Benzon H, Raja S, Molloy RE, Strichartz G, eds. Essentials of Pain Medicine and Regional Anesthesia.
New York, USA. Churchill Livingstone, 1999: 159-163.
5. Twycross R. Opioids. In: Wall P, Melzack R, eds. Textbook of Pain.
Edinburgh, UK: Churchill Livingstone, 1999: 1187-1214.
6. Page S. Opioid receptors. In: Benzon H, Raja S, Molloy RE, Strichartz G, eds. Essentials of Pain Medicine and Regional Anesthesia.
New York, USA. Churchill Livingstone, 1999: 48-50.
7. Kehlet H, Rung GW, Callesen T. Postoperative opioid analgesia: time for a reconsideration? J Clin Anesth
8. Kehlet H, Dahl JB. The value of 'multimodal' or 'balanced analgesia' in postoperative pain treatment. Anesth Analg
9. Buggy DJ, Wall C, Carton EG. Preoperative or postoperative diclofenac for laparoscopic tubal ligation. Br J Anaesth
10. Bunemann L, Thorshauge H, Herlevsen P, et al.
Analgesia for outpatient surgery: placebo versus naproxen sodium (a non-steroidal anti-inflammatory drug) given before or after surgery. Eur J Anaesthesiol
11. Patrignani P, Sciulli M, Manarini S. COX-2 is not involved in thromboxane biosynthesis by activated human platelets. J Physiol Pharmacol
12. Rosenblum M, Weller RS, Conrad PL, et al.
Ibuprofen provides longer lasting analgesia than fentanyl after laproscopic surgery. Anesth Analg
13. Brooks PM, Day RO. Nonsteroidal antiinflammatory drug differences and similarities. N Engl J Med
14. Simon LS, Weaver AL, Graham DY, et al.
Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA
15. Bensen WG, Fiechtner JJ, McMillen JI, et al.
Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc
16. Day R, Morrison B, Luza A, et al.
A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study Group. Arch Intern Med
17. Emery P, Zeidler H, Kvien TK, et al.
Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: a randomised double-blind comparison. Lancet
18. McKenna F, Borenstein D, Wendt H, et al.
Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol
19. Sisson C. Tramadol. In: Benzon H, Raja S, Molloy RE, Strichartz G, eds. Essentials of Pain Medicine and Regional Anesthesia.
New York, USA: Churchill Livingstone, 1999: 59-62.
20. Liu S. Local anesthetics and analgesia. In: Ashburn M, Rice L, eds. The Management of Pain.
Philadelphia, USA. Churchill Livingstone, 1998: 141-169.
21. Strichartz G. Neural physiology and local anesthetic action. In: Cousins M, Bridenbaugh P, eds. Neural Blockade in Clinical Anestheisa and Management of Pain.
Philadelphia, USA. Lippincott-Raven, 1998: 35-54.
22. Fogarty DJ, O'Hanlon JJ, Milligan KR. Intramuscular ketorolac following total hip replacement with spinal anaesthesia and intrathecal morphine. Acta Anaesthesiol Scand
23. Fragen RJ, Stulberg SD, Wixson R, et al.
Effect of ketorolac tromethamine on bleeding and on requirements for analgesia after total knee arthroplasty. J Bone Joint Surg Am
24. Rawal N. 10 years of acute pain services - achievements and challenges. Reg Anesth Pain Med
25. Sinatra R. Acute pain management and acute pain services. In: Cousins M, Bridenbaugh P, eds. Neural Blockade in Clinical Anesthesia and Management of Pain.
Philadelphia, USA. Lipincott-Raven, 1998: 793-835.
26. Apfelbaum J, Gan T, Chen C. Current hospital acute pain management practices: patient education and post-discharge follow-up [Abstract]. American Pain Society. J Pain
2000; 1 (Part 2).
27. Apfelbaum J, Gan T, Chen C. Patient postoperative pain experience: outpatient surgery survey. American Society of Anesthesiologists Annual Congress [abstract A-1]. Anesthesiology
28. Harrison D, Sinatra RS, Morgese L, et al.
Epidural narcotic and patient-controlled analgesia for post-Cesarean section pain relief. Anesthesiology
29. Eisenach J, Grice S, Dewan D. Patient-controlled analgesia following Cesarean section: a comparison with epidural and intramuscular narcotics. Anesthesiology
30. Miaskowski C, Crews J, Ready B, et al.
Anestheisa-based pain services improve the quality of postoperative pain management. Pain
31. Wong HY, Benzon H. Outcome studies in postoperative pain control. In: Benzon H, Raja S, Molloy RE, Strichartz G, eds. Essentials of Pain Medicine and Regional Anesthesia.
New York, USA. Churchill Livingstone, 1999: 167-170.
32. Buggy DJ, Wall C, Carton EG. Preoperative or postoperative diclofenac for laparoscopic tubal ligation. Br J Anaesth
33. Bunemann L, Thorshauge H, Herlevsen P, et al.
Analgesia for outpatient surgery: placebo versus naproxen sodium (a non-steroidal anti-inflammatory drug) given before or after surgery. Eur J Anaesthesiol
34. Sevarino FB, Sinatra RS, Paige D, et al.
Intravenous ketorolac as an adjunct to patient-contolled analgesia (PCA) for managment of postgynecologic surgical pain. J Clin Anesth
35. Sevarino FB, Sinatra RS, Paige D, et al.
The efficacy of intramuscular ketorolac in combination with intravenous PCA morphine for postoperative pain. J Clin Anesth
36. Rang HP, Urban L. New molecules in analgesia. Br J Anaesth
37. Perkins M, Campbell E, Dray A. Antinociceptive activty of the bradykini B1 and B2 receptor antagonists, des-Arg9, (Leu8)-BK and HOE 140, in two models of persistent hyperalgesia in the rat. Pain
38. Sawrutz D, Salvino J, Dolle R, et al.
WIN 64388 is a bradykinin B2 recptor antagonist. Proc Natl Acad Sci USA
39. Steranka L, De Haas C, Vavrck R, et al.
Antinociceptive effects of bradykinin antagonists. Eur J Pharmacol
40. Steranka L, Manning D, De Haas C, et al.
Bradykinin as apain mediator: receptors are localized to sensory neurones, and antagonists have analgesic actions. Proc Natl Acad Sci USA
41. Beiche F, Scheuerer S, Brune K, et al.
Up-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett
42. Seibert K, Zhang Y, Leahy K, et al.
Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA
43. Dinarello C. Role of interleukin-1 and tumor necrosis factor insystemic responses to infection and inflammation. In: Galllin J, Goldstein I, Snyderman N, eds. Inflammation: Basic Principles and Clinical Correlates.
New York, USA. Raven, 1992: 123-138.
44. Fukouka H, Kawatani M, Hisamitsu T, et al.
Cutaneous hyperalgesia induced by peripheral injection of inter-leukin-1 beta in the rat. Brain Res
45. Ferreira SH, Lorenzetti BB, Poole S. Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol
46. Lee J, Badger A, Griswold D, et al.
Bicyclic imidazolines as a novel class of cytokine biosynthesis inhibitors. Ann NY Acad Sci
47. Nakanishi S. Mammalian tachykinin receptors. Ann Rev Neurosci
48. Levine JD, Fields H, Basbaum A. Peptides and the primary afferent nociceptor. J Neurosci
49. Otsuka M, Yanagisawa M. Pain and neurotransmitters. Cell Mol Biol
50. McMahon FG, Lewin J, Wall PD Central hyperexcitability triggered by noxious inputs. Curr Opin Neurobiol
51. Theriault E, Otsuka M, Jessell T. Capsaicin-evoked release of substance P from primary afferent sensory neurons. Brain Res
52. Snider R, Constantine J, Loewe J, et al.
A potent non-peptide antagonist of the substance p (NK1) receptor. Science
53. Spande T, Garraggo H, Edwards M, et al.
Epibatidine: a novel (chloropyridyl) azabicycloheptane with potent analgesic acitivyt from an Equadoren poison frog. J Am Chem Soc
54. Fisher M, Huangfu D, Shen T, et al.
Epibatidine, an alkaloid from the poison frog Epipedobates tricolour, is a powerful ganglionic depolarizing agent. J Phamacol Exp Ther
55. Vane JR, Bakhle Y, Botting R. Cyclooxygenases 1 and 2. Ann Rev Pharmacol Toxicol
56. Needleman P, Isakson PC. The discovery and function of COX-2. J Rheumatol
57. Dubois RN, Abramson SB, Crofford L, et al.
Cyclooxygenase in biology and disease. FASEB J
58. Huang Z, Massey J. Differential regulation of cyclooxygenase-2 (COX-2) mRNA stability by interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) in human in vitro
differentiated macrophages. Biochem Pharmacol
59. Porreca E, Reale M, Febbo CD, et al.
Down-regulation of cyclooxygenase-2 (COX-2) by interleukin-receptor antagonist in human monocytes. Immunology
60. Kang RY, Freire-Moar, Sigal E, et al.
Expression of cyclooxygenase-2 in human and an animal model of rheumatoid arthritis. Br J Rheumatol
61. Vanegas H, Schaible HG. Prostaglandins and cyclooxygenases in the spinal cord. Prog Neurobiol
62. Smith CJ, Zhang Y, Koboldt CM, et al.
Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA
63. Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci USA
64. Woolf CJ, Salter MW Neuronal plasticity: increasing the gain in pain. Science
65. Hay C, de Belleroche J. Carrageenan-induced hyperalgesia is associated with increased cyclooxygenase-2 expression in spinal cord. Neuroreport
66. Hay CH, Trevethick MA, Wheeldon A, et al.
The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia. Neuroscience
67. Malmberg AB, Yaksh TL. Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formal test in the rat. J Pharmacol Exp Ther
68. Cryer B, Feldman H, Agrawal N. Cyclooxygenase-1 ancyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med
69. Leese PT, Hubbard RC, Karim A, et al.
Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol
70. Silverstein FE, Faich G, Goldstein JL, et al.
Gastro-intestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA