The effective management of acute pain following surgery is a key goal for anaesthetists, surgeons and nursing specialists. However, despite our best efforts, many postoperative surgical patients receive inadequate pain management, not only due to limitations of currently available treatment options, but also because of inadequate assessment techniques and insufficient information on drug tolerance/addiction. In recent years, the World Health Organization (WHO) has proposed guidelines for the selection of drug regimens for the management of cancer pain . The basic premise put forward was that pain intensity should serve as the principal subjective measure in determining the treatment used, which can also be applied in the management of acute pain such as postoperative pain, and other forms of non-malignant chronic pain. According to these guidelines, non-opioid analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol) should be the first choice for treatment of mild-to-moderate pain. In the event that these agents do not provide adequate pain control, combinations of such non-opioid analgesics and opioid agents should be used. The potency of the opioid should be determined by the level of pain intensity so that low-potency opioids should be prescribed initially and high-potency opioids used for severe pain.
Current treatment options for the management of acute pain
Opioid analgesics and conventional NSAIDs dominate current treatment strategies for acute pain. Alternative pain-management strategies include combinations of analgesic products, including opioids, NSAIDs, local anaesthetics, and nerve and neuraxial blocks. The combination of different drug classes in this type of multimodal treatment strategy can provide additive and sometimes synergistic analgesic effects, while the reduction in use of any one single agent has the benefit of reducing the extent of any potential side-effects it may pose. Conversely, increasing the number of drugs prescribed to a patient brings with it the risk of a broader spectrum of side-effects. Thus, there is a need for novel treatment options with improved safety profiles that are effective in treating postoperative pain when administered alone or in combination.
Opioids are currently among the most commonly used and effective analgesics available for the management of moderate-to-severe pain and are known for their potency and speed of onset of action . They represent a diverse class of agents, and there exists great variation in potency, the speed of onset, the duration of action and the optimal route of administration. Their effects are based on interaction with endogenous opioid receptors, namely the OP1, OP2 and OP3 receptors; most commercially available opioids bind several OP1 subreceptors . There is a high degree of variability in patient response to opioids, which is thought to result from differences in receptor subtypes. Changes at receptor level may also account for opioid tolerance that occurs with long-term use of these agents. Other drawbacks of opioid use are the wide range of potential side-effects, including CNS depression and sedation, respiratory depression, changes in gastrointestinal motility leading to constipation or diarrhoea, nausea and vomiting, urinary retention and pruritus [4-7]. These side-effects are common and can limit the use of opioids despite their analgesic efficacy, in postoperative analgesia. Postoperative surgical patients who have been prescribed opioids will often request less analgesia from hospital staff, or underadminister patient-controlled analgesia (PCA) because the medication itself makes them feel ill. Therefore, opioids are often co-administered with other analgesics such as anti-inflammatory drugs to maximize pain relief while reducing the amount of opioid required postoperatively [7,8].
NSAIDs are perhaps the most commonly used agents in the management of acute pain, including postoperative pain, ranging from mild pain to the most severe [9-12]. They act through the inhibition of the two known isoforms of cyclo-oxygenase (COX-1, COX-2), the key enzyme in the metabolism of prostaglandins, providing effective anti-inflammatory and analgesic activity through the inhibition of COX-2, but also causing impairment of platelet function and upper gastrointestinal side-effects due to inhibition of COX-1 [13,14]. In recent years, anti-inflammatory agents that selectively inhibit COX-2 at therapeutic doses have been introduced [15-18]. These agents effectively reduce pain and inflammation, but are associated with significantly reduced upper gastrointestinal toxicity and platelet dysfunction compared with conventional NSAIDs.
There is a wide variety of other non-opioid analgesics available. Acetaminophen is probably the most widely used analgesic worldwide. It has the advantage of an extremely good safety profile at therapeutic doses and causes none of the side-effects associated with opioids or indeed the gastrointestinal and platelet complications observed with NSAIDs. However, even at therapeutic doses, it is not a strong analgesic and often has to be used in combination with other agents for anything more than mild-to-moderate pain.
Tramadol is often classified as an opioid analgesic due to its weak binding of OP1, OP2 and OP3 receptors. However, it also inhibits norepinephrine and serotonin uptake, possibly acting as an antidepressant in some patients. It is believed that both non-opioid and opioid mechanisms contribute to the antinociceptive effects of tramadol . Although serious opioid-related side-effects such as respiratory depression are not associated with tramadol, it causes other side-effects such as sedation, nausea and constipation.
Local anaesthetics can block peripheral nerve function via several mechanisms, e.g. reducing sodium ion transport by interacting with the surrounding membrane or by altering membrane fluidity . Central neuraxial blocks via spinal or epidural administration involve similar mechanisms and may also inhibit synaptic transmission at pre- and postsynaptic neural junctions. A major drawback of using such treatments for analgesia is tachyphylaxis, i.e. reduced efficacy following repeated injections of the same dose of local anaesthetic . This decreased efficacy may arise from spinal cord sensitization, or anatomical changes such as peripheral oedema or microhaemorrhage. Furthermore, these agents can be associated with dose-related CNS and cardiovascular toxicity, such as CNS depression or excitation and seizures (depending on the size of the dose), hypotension, bradycardia, and, in extreme cases, cardiovascular collapse .
Multimodal analgesia involves the use of combinations of analgesic agents, such as opioids, and anti-inflammatory agents or acetaminophen, with different yet complementary modes of action. There is some evidence that the use of anti-inflammatory agents in combination with opioids may have additive analgesic properties . This potentiation allows prescription of lower doses of each agent, thereby maintaining the same level of analgesia, or in some instances improving pain relief, while reducing the severity of dose-related side-effects associated with the use of single agents. A model of a multimodal treatment strategy is shown in Figure 1, in which an opioid is used in combination with NSAIDs, acetaminophen or nerve blocks to reduce postoperative pain . The disadvantage of this multimodal analgesia is that the range of potential side-effects is increased. Thus, in the case of co-administration of traditional NSAIDs with opioids, one may reduce levels of sedation, nausea, vomiting, etc. normally associated with opioid use, but the risk of gastrointestinal toxicity and the potential for bleeding complications characteristic of NSAIDs are introduced. The use of injectable NSAID formulations is often limited by their potential for significant adverse effects. For example, ketorolac, currently the only injectable NSAID available in the USA, is associated with significant bleeding complications that prohibit its intraoperative use [22,23]. Injectable forms of acetaminophen are currently not available in many countries and administration of nerve blocks requires technical skill and specialized equipment. However, the premise of multimodal analgesia is increasingly favoured and the introduction of effective analgesics that have an improved safety profile, and which are easily administered, will be of great benefit in this therapeutic strategy.
Unmet needs in the management of acute pain
A greater interest in pain pathophysiology and the management of pain in postoperative patients has arisen in recent years, and there is a consensus in the medical profession that there is a need for technology and drugs that provide improved pain management. However, despite our best efforts, many patients with surgical pain do not receive adequate pain relief . There are several factors that contribute to the undermanagement of acute pain such as the lack of formal education in pain management, mistaken beliefs and fears among clinicians about potential opioid addiction and drug tolerance, inadequate pain assessment, and traditional emphasis on 'PRN' (per re na ta) dosing [24,25]. Problems can arise with the latter owing to patients' reticence in requesting pain medication when they require it. Alternative administration techniques such as PCA have gone some way to improving the undermanagement of pain, but this method involves complex and expensive technology and equipment that requires specialist-directed services.
Recent health outcome studies have demonstrated that postoperative pain is still frequently undermanaged [26,27]. In 1999, a geographically representative study was carried out among 250 adult patients in the USA, who had recently undergone a surgical procedure, to determine how well their pain had been managed and patient satisfaction with their treatment . The questionnaire from this study was a modified version of a similar study carried out in 1993, and findings from the two studies were compared retrospectively. Over 80% of patients reported experiencing pain postoperatively, often being of severe or extreme pain (Fig. 2). Furthermore, when compared with the results of the 1993 study, there was no significant difference in the levels of pain experienced, indicating that acute pain management had not significantly improved in the intervening period. In the same study, ambulatory patients reported a worsening of pain following hospital discharge compared with their pain levels immediately before discharge (Fig. 3). In another survey carried out in 2000, physicians involved in pain management in 225 hospitals in the USA were interviewed on their current acute pain management practices . Significantly, approximately 20% of institutions did not provide their surgical patients with information or counselling about their postoperative pain management. Clearly, there is room for improvement in all aspects of postoperative patient care and pain management.
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.
New approaches to acute pain management
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.
It is well known that the prostanoids PGE2 and PGI2 are produced in excess in inflamed tissue and in the CNS in response to inflammatory stimuli and they play a key role in the mediation of inflammatory pain [10,11,41]. Conventional NSAIDs exert their therapeutic action through inhibition of COX-2, but are associated with adverse platelet and gastrointestinal effects through their non-selective inhibition of COX-1 [13,14]. It was therefore hypothesized that COX-2-selective inhibitors that selectively inhibited COX-2 at therapeutic doses but which spared COX-1 would provide effective analgesia while reducing the side-effect profile associated with conventional NSAIDs [9-11,42]. Proinflammatory cytokines such as interleukin 1β (IL-1β), interleukin 8 (IL-8) and tumour necrosis factor α (TNFα) are produced early in inflammatory responses and are potent hyperalgesic agents, acting in the peripheral and central nervous systems [43-45]. Peptide receptor antagonists for the IL-1β receptor were shown to block inflammatory hyperalgesia in animal models , and cytokine-suppressive anti-inflammatory drugs were shown to inhibit production of IL-1β and TNFα .
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.
COX-2 technology-a new approach to pain management
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.
Efficacy and safety profile of COX-2-selective inhibitors
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).
Thromboxane A2 (TxA2) is the primary metabolite of COX-1-mediated metabolism of arachidonate in platelets . It plays an important role in platelet aggregation and blood clotting. COX-1 is the only COX isoform expressed in platelets, and as NSAIDs are all non-selective inhibitors of COX isoforms, all are associated with the inhibition of platelet aggregation and with prolonged bleeding [14,68]. In clinical studies, platelet aggregation responses were not affected by celecoxib, whereas conventional NSAIDs, naproxen, ibuprofen and diclofenac, caused significant inhibition of platelet aggregation and prolonged bleeding compared with placebo (Fig. 6a). Additionally, there were no significant differences between celecoxib and placebo in the rates of gastroduodenal ulceration in osteoarthritis and rheumatoid arthritis patients, whereas naproxen caused significantly increased gastroduodenal ulceration compared with both celecoxib and placebo (Fig. 6b)[14,70].
Conclusions and discussion
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