The anesthesiologist has a central role in the management of acute postoperative pain, and effective management has been clearly demonstrated to improve clinical outcomes (1,2). Acute pain can rapidly evolve into chronic pain, and the two should not be viewed as separate entities (3). Failure to achieve effective analgesia is a major predictive factor for the conversion of acute postoperative pain to chronic pain after several different types of surgery (4).
Traditionally, opioids and local anesthetics have been the pharmacological foundation for postoperative pain management; however, optimization has been difficult because of anxieties regarding deleterious side effects. Opioids may cause respiratory depression, oversedation, and prolongation of postoperative ileus. Regional anesthetic techniques are limited by the requirement for special monitoring and the irreversibility of neuronal blockade once it is instituted.
The effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) in alleviating pain and reducing requirements for opioids in the postoperative period has been well documented (5–7), but concerns regarding gastropathy, renal dysfunction, and hemostatic defects have limited their use. There is further anxiety because fasting and the frequent prevalence of hypovolemia in the postoperative period may potentiate gastric and renal side effects.
Do anesthesiologists underuse NSAIDs as perioperative analgesics because of exaggerated anxieties regarding side effects and inadequate information regarding mode of action? This review article describes prostaglandin (PG) biosynthesis and the central role of cyclooxygenase (COX) expression in pain perception, and then it focuses on the potential side effects of COX inhibition.
Goals of Postoperative Analgesia
The goal of postoperative pain relief is to achieve optimal analgesia, facilitating a speedy return to normal physiological organ function with minimal side effects. Anesthesiologists must also try to reduce the incidence of chronic pain after surgery by effective treatment of acute postoperative pain. Minimization of opioid and local anesthetic side effects is a major consideration, and here NSAIDs have great potential. This process begins at the preoperative assessment, when the anesthesiologist must identify patients at increased risk of NSAID-induced complications. Although renal failure, allergy, and late pregnancy are absolute contraindications, a history of peptic ulcer disease, congestive cardiac failure, or cirrhosis, previous thrombosis, and concomitant corticosteroid therapy require further consideration before being classed as contraindications. A history of NSAID consumption for other conditions, such as arthritis, is reassuring, and a normal creatinine clearance will allay fears regarding postoperative renal failure.
In 1971, Vane (8) demonstrated that aspirin exerted its effects by inhibiting PG synthesis via inhibition of the enzyme COX. In 1991 the DNA sequence in human tissue for COX-1 was identified and, for COX-2, in 1992 (9,10). The two different isoforms are now called COX-1 and COX-2 (11).
Arachidonic acid is released from cell membrane phospholipid by the activity of phospholipase A2 (PLA2). PLA2 is essential for PG synthesis, and a synchronous regulation of PLA2 and COX has been demonstrated (12,13). The enzymatic activity of COX on arachidonic acid forms PGH2. Newly generated PGH2 is then converted to PGD2, PGE2, and PGF2α, prostacyclin (PGI2), and thromboxane A2 (TXA2) by tissue-specific isomerases (11,14). All prostanoid synthesis is dependent on the action of COX on arachidonic acid, although the effect at the cellular level is cell specific. Endothelial cells synthesize mainly PGI2, which inhibits platelet aggregation, and platelets synthesize mainly TXA2, which has a proaggregational effect.
Recent work on rat tissue has also demonstrated different levels of expression of COX-1 and COX-2 messenger RNA (mRNA) in different organs. COX-1 mRNA was expressed in the liver, lung, and kidney, but not the heart, whereas COX-2 mRNA was expressed in the lung, heart, and kidney, but not the liver. This suggests that COX-1 and COX-2 have a regulatory physiological role that is organ specific. This may also indicate that certain organs will be more sensitive to COX inhibition than others (15).
COX and Pain
Surgical tissue trauma results in the release of a vast number of inflammatory mediators, including prostanoids. These mediators affect nociceptors, altering their firing threshold and sometimes causing direct stimulation (16). COX-2 plays a key role in the central neurological response to inflammation. Immunoreactivity studies have demonstrated the presence of COX-2 in the superficial dorsal horn of the spinal cord (17,18), and PG receptors are found in dorsal root ganglia (19,20). It is at this level that the afferent sensory nerve axons enter the spinal cord and spinal nociceptive processing begins.
Central neurons generate both PGE2 and PGI2 in response to peripheral injury (21), and intrathecal application of PGs induces pain behavioral responses (22,23). In a rat model, peripheral injury has resulted in COX-2 induction in the dorsal root neurons (21,24–27). Moreover, intrathecal COX inhibition has been demonstrated to reduce hyperalgesic responses to thermal injury in rats (28). COX-1 and -2 are found in brain tissue, with COX-2 mRNA being demonstrated in the resting condition (29). Electroconvulsive seizures induce COX-2 mRNA in rat brain, and this was found to be N-methyl-d-aspartate (NMDA) dependent, because the glutamate antagonist MK-801 abolished this response. COX-2 was also colocalized with glutamate in the dendrites of excitatory neurons (30). NMDA receptor activation results in increased prostanoid synthesis (31).
Neuronal depolarization is mediated by the excitatory amino acids glutamate and aspartate. These excitatory amino acids are present in many types of sensory neurons and exert their effects initially via α-amino-3-hydroxy-5-methyl isoxazolepropionic acid (AMPA) and kainate channels (32). Excitatory amino acid activation of AMPA and kainate channels leads to activation of NMDA receptors, with resultant long-lasting partial depolarization; subsequent low-intensity stimuli, which previously were unable to generate an action potential, can then do so (33). The activation of NMDA receptors is crucial for both acute pain perception and for central sensitization and windup to occur, potentially leading to chronic pain (34,35). Spinal NMDA activation causes acute mechanical nociception (through activation of COX-2 enzymes) and hyperalgesia (as a result of peripheral inflammation via upregulation of COX-2) (36). NMDA receptors have also been linked to COX-2 expression in a focal ischemia model, because the induction of COX-2 by ischemia is inhibited by an NMDA antagonist (37). As with NMDA receptors, AMPA activation seen after global ischemia results in prolonged neuronal COX-2 expression (38). The effects of NMDA and AMPA activation may be COX-2 dependent, because intrathecal injection of a COX-2 inhibitor inhibits the development of hyperalgesia induced by intrathecal injection of either NMDA or AMPA in a dose-dependent manner (39). Thus, both AMPA and NMDA receptor activation are linked to COX-2 expression with resultant nociception (Fig. 1).
There is a distinct neurochemical response in acute and persistent pain. It is interesting to note that rat spinal cord sections from an adjuvant-induced arthritis model have demonstrated the induction of COX-2 at 22 days (40). This is further evidence in support of the concept that the neurochemistry of the central spinal cord is altered in a specific fashion after an insult and that this effect may be prolonged (41,42). Thus, COX-2 expression induced by surgery may last longer than previously thought, and this raises the possibility of persistent COX-2 expression being a possible factor in the etiology of chronic pain after surgery.
Gastrointestinal Effects of COX
Clinically the most common side effects of NSAIDs are seen in the gastrointestinal system (43,44). The risk of NSAID-induced peptic ulcer complications results in approximately 1.25 additional hospitalizations per 100 patient-years on average. However, this may be affected by the presence of Helicobacter pylori and varies among different NSAIDs and dose regimens. Small-dose ibuprofen has been reported to cause fewer gastrointestinal complications than other NSAIDs. The risk of gastropathy is increased in patients who are elderly, have a history of peptic ulcer disease, or take concomitant corticosteroids or anticoagulants (45).
There has been great interest in the cytoprotective role of PGs in the gastrointestinal system. In particular, PGE2 and PGI2 have been shown to increase mucous production and inhibit acid secretion in the stomach (46). The healing of peptic ulcers is enhanced by COX-2-dependent PG synthesis (47–49). Thus, it would seem that inhibition of PG synthesis by NSAIDs might provide a possible explanation for NSAID-induced peptic ulceration. It has been postulated that NSAID inhibition of COX-1 biosynthesis in the stomach is the key factor responsible for gastric erosion formation (50). However, it has been demonstrated, in mice with a disrupted COX-1 gene, that the associated gastric PG synthesis reduction was not associated with gastric damage (51). H. pylori infection in the stomach is associated with peptic ulcer disease, and it is interesting that even in the presence of H. pylori colonization, COX-2-dependent PG synthesis is present and may be protective (52).
The use of selective COX-2 inhibitors in patients with osteoarthritis and rheumatoid arthritis has resulted in less gastric erosion than that seen when using earlier NSAIDs at dosages that have an antiinflammatory effect (53,54). These observations again support the hypothesis that it is COX-1 inhibition that leads to gastric erosion. However, recent evidence suggests that selectively inhibiting either COX-1 or COX-2 in isolation does not cause gastric erosion. Inhibition of both isoforms is to some extent required for gastric mucosal damage to occur (55). The mechanism of NSAID-induced gastric mucosal ulceration is unclear, but it probably involves an NSAID-induced adherence of leukocytes to the vascular endothelium in the gastric microcirculation (56) in combination with a reduction in gastric blood flow (57).
There has always been a concern that patients may be exposed to an increased risk of gastrointestinal and renal side effects from the use of NSAIDs for postoperative analgesia, because of postoperative fasting and the relatively frequent incidence of hypovolemia after major surgery. However, the newer NSAIDs have a greater COX-2 inhibitory effect, and although there are still some COX-1 inhibitory effects, there is growing clinical evidence of the superior tolerability of the more selective COX-2 inhibitors, with the Vioxx Gastrointestinal Outcome Research Group study demonstrating a 60% reduction in perforation, obstruction, and bleeding (58–64).
Renal Effects of COX
Renal complications of NSAID use include acute renal failure, hyperkalemia, water and sodium retention, nephrotic syndrome, and interstitial nephritis (65,66). It is interesting to note that in the United States, prescription NSAID use results in 25 excess hospitalizations because of renal failure per 10,000 years of use in patients older than 65 yr. This suggests that NSAID-induced complications in older people are uncommon (67). However, it may not be possible to extrapolate these encouraging data to the perioperative period. COX-2 is constitutively expressed in the kidney (68), and the role of PGs in renal homeostasis is complex. PGI2 and PGE2 are the major mediators, with PGI2 found in the renal cortex and glomeruli and PGE2 in the juxtamedullary glomeruli and medullary portion of the collecting ducts. They produce arteriolar dilation, increasing renal perfusion and sodium excretion, while reducing medullary tonicity and antidiuretic hormone effectiveness and stimulating renin secretion. PGI2 attenuates podocyte constriction, thereby maintaining glomerular filtration rate (GFR) in the presence of angiotensin-2 and antidiuretic hormone. TXA2 is found in the glomeruli, where it causes vasoconstriction and podocyte contraction and thus reduces glomerular filtration. PGF2α enhances tubular sodium and water excretion (69). Tubulo-glomerular feedback is an important mechanism of autoregulation for renal perfusion. The macula densa is the sensing part of this mechanism, and its activity requires a COX-2 pathway for signaling (70). The effect of a selective COX-2 inhibitor (nimesulide) was compared with that of a nonselective inhibitor (meclofenamate) in dogs with normal and small sodium intake. The effects on renal hemodynamics, urinary sodium excretion, and fractional lithium excretion were quite different, suggesting that COX-2-derived PGs play an important role in sodium excretion and renal hemodynamics (71). Endogenous PGs have been demonstrated not to affect renal hemodynamics under the pressor effects of prolonged angiotensin-2 exposure. In fact, after significant renal injury, prolonged therapy with selective COX-2 inhibition decreased proteinuria and retarded further renal injury (72). However, renal PGs do modulate the effects of subpressor angiotensin-2 levels by reducing vasoconstriction and enhancing tubular sodium absorption. This suggests that under the threat of hypoperfusion, endogenous renal PGs ensure that the renin-angiotensin system will work to maintain both renal and systemic perfusion. In patients with chronic renal failure, residual function is PG dependent, and here NSAIDs may cause rapid deterioration (69).
Sodium retention and edema are found in 5% of the population taking NSAIDs (73). Hyperkalemia is noted in up to 46% of patients because of decreased renin secretion (74).
Clinical trials have produced inconsistent results; one study demonstrated no GFR reduction in patients with chronic renal failure taking celecoxib or naproxen, whereas another demonstrated no difference in GFR reduction between patients taking rofecoxib or indomethacin (75–78). Patients with cardiac failure, cirrhosis, or hypertension have a predisposition to prerenal renal failure. The anesthesiologist should view these patients as being at increased risk for NSAID-induced renal failure. A recent study demonstrated that celecoxib caused less edema and destabilization of blood pressure control than rofecoxib in hypertensive patients and suggested that these patients should be monitored for cardiorenal events if they are prescribed selective COX-2 inhibitors (79). It is interesting that both celecoxib and rofecoxib have been reported to cause acute renal failure (80,81). The effect of diclofenac and ketorolac on perioperative renal function has been investigated in a rat model. The administration of the NSAIDs did not induce renal dysfunction. However, if combined with gentamicin, both NSAIDs produced marked deterioration in renal function, with associated pathologic changes in renal structure (82,83). An interaction between ibuprofen and gentamicin resulting in renal failure has also been reported in humans (84). This evidence suggests that the coadministration of aminoglycosides with NSAIDs in the perioperative period may be a significant risk factor for inducing renal failure.
PGs and the Cardiovascular System
Myocardial ischemia results in ischemic preconditioning, which protects myocardial cell function from further ischemic episodes. Evidence suggests that upregulation of nitric oxide is required for preconditioning (85), and this is associated with a simultaneous induction of COX-2 (86). COX-2-mediated cardioprotection occurs in the later phases of preconditioning and is due to PGE2 and PGΙ2 synthesis (87). These PGs attenuate myocardial stunning (88) and reduce infarct size (89). The cytoprotective effects of PGE2 and PGΙ2 are due to activation of adenosine triphosphate-sensitive potassium channels (89) and a reduction in myocardial neutrophil infiltration (90). Although these animal data suggest that COX-2 inhibition may worsen myocardial performance in the presence of ischemia, there is now evidence that COX-2 inhibition reduces atherosclerosis. Atherosclerosis is now viewed as a chronic inflammatory condition (91) in which COX-2 is upregulated (92). COX-2 inhibition markedly reduces neointimal formation in an animal model of atherosclerosis (93).
There is concern regarding the effect of COX inhibition on renal artery tension. PGs have different effects on vascular smooth muscle; TXA2 causes vasoconstriction and platelet aggregation (94), whereas PGI2 has the opposite effect (95). The in vitro vasoconstriction caused by angiotensin-2 in the human internal mammary artery is enhanced by, but not dependent on, eicosanoid biosynthesis produced from the COX pathway (96). Therefore, vascular tension may be affected by COX inhibition, but neither isoform is predominant or is the sole factor affecting tension.
Postoperative Nausea and Vomiting
Work in conscious piglets has demonstrated that activation of the medullary vomiting center involves PGs. Lipopolysaccharide-induced emesis was abolished by COX inhibition by using both meloxicam and indomethacin, when these were administered before the lipopolysaccharide (97).
COX inhibition with NSAIDs may increase the risk of vascular thrombus formation by upsetting the balance of pro- and antiplatelet aggregation effects: TXA2 synthesis is primarily a COX-1-induced effect, and PGI2 is a COX-2 effect. Four patients with Raynaud’s syndrome developed thrombotic complications after receiving COX-2 inhibition as part of their treatment (98). This side effect is unreported with the nonselective COX inhibitors. Although platelet dysfunction occurs with COX-1 inhibition, there has been no prospective randomized control clinical trial demonstrating an increase in hemorrhage in patients who have received NSAIDs.
PG Interactions with Anesthetic Agents
Lipopolysaccharide administration enhances the hyperemic response. However, pretreatment with NS-398 attenuated these observed effects in rats when they were anesthetized with halothane, and the effects were abolished by aminoguanidine (an inducible nitric oxide synthase inhibitor) and dexamethasone. These results suggest that halothane-induced cerebrovascular hyperemia is achieved through a nitric oxide- and COX-dependent pathway (99).
PGs and Asthma
Aspirin and NSAIDs cause bronchoconstriction in approximately 10% of asthmatic patients, although it is interesting that they relieve it in approximately 0.3% of patients (100). This illustrates the complexity of COX interaction in the lungs. Recent work has delineated possible explanations for aspirin-induced asthma (AIA), and these explanations will facilitate improved NSAID selection by anesthesiologists in this difficult population. COX inhibition diverts arachidonic acid metabolites to the lipoxygenase pathway, with an associated reduction in PGE2 synthesis and an increase in cysteinyl leukotrienes. Patients with AIA have increased cysteinyl leukotriene levels because of enzymatic overactivity, which can be fueled by more leukotrienes from COX inhibition (101). There is growing evidence that AIA is due to COX-1 inhibitory effects and that selective COX-2 inhibitors are relatively safe to use in this population (102,103)
Preemptive Analgesia with NSAIDs
The concept of pain prevention, as opposed to pain treatment, is very attractive to anesthesiologists, and here NSAIDs have a role to play. Inhibition of COX expression prevents AMPA and NMDA receptor activation and ascending spinal “pain traffic.” Although support for preemptive analgesia waned in the latter half of the 1990s because of conflicting trial results, renewed interest has developed as a greater understanding of the mechanism of central sensitization has been forthcoming. One of the major problems is agreement on the definition of preemptive analgesia. It may be defined as treatment that prevents the establishment of central sensitization caused by incisional and inflammatory injuries during both the surgical and initial postoperative periods (104). Thus it is clear that treatment must be established long enough before surgery to have its full pharmacodynamic effect. Therefore, COX expression must be inhibited before surgery and during the initial postoperative period, because the response to surgery may last longer than originally thought. Work recently completed demonstrates a clear role for spinal COX-2 expression in postoperative nociception in humans (105). There is growing support for the concept that NSAIDs’ analgesic site of action is at the spinal level (106). Therefore, the administered NSAID must have achieved COX inhibition spinally before the surgical stimulus. IV NSAID formulations are attractive in facilitating rapid plasma levels in the perioperative period, and this will minimize pharmacokinetic attenuation of the drug effect, which may occur with other routes of administration. Ketorolac and tenoxicam are available for IV administration, and preemptive analgesia has been demonstrated with both drugs (107,108). With preemptive analgesia now clearly defined, further research is eagerly awaited to decide whether this attractive analgesic modality should become part of everyday practice.
COX-1/COX-2 Selectivity of NSAIDs
Several techniques can be used to establish the selectivity ratios for different NSAIDs, including whole-blood assays for serum TXA2 (COX-1) and plasma PGE2 (COX-2), transfected cells, purified recombinant enzyme, and drug inhibition of human gastric PGs. There may be significant variations in selectivity, depending on the technique used, although drug inhibition of human gastric PGs may become the “gold standard”(43).
The actual prevalence of side effects from prescription NSAIDs is small, and in the postoperative pain relief scenario they are excellent analgesics; standard doses of diclofenac give analgesia equivalent to 10 mg of IM morphine (109). The analgesic efficacy of selective COX-2 inhibitors is equal to that of the nonselective NSAIDs, with significantly less potential for COX-1-induced complications (110). There has been no prospective, randomized, controlled trial that demonstrates that patients who received NSAIDs have an increased risk of peptic ulceration, renal dysfunction, or hemostatic defect in the postoperative period compared with patients who did not receive NSAIDs. Despite the theoretical risk of drug interactions, there is a lack of supporting evidence for drug interactions involving selective COX-2 inhibitors (111). It is clear that COX-2 plays a central role in pain perception. The advent of NSAIDs that selectively inhibit COX-2 may minimize COX-1-dependent side effects while offering analgesia, a reduction in opioid requirements, and the potential to reduce the incidence of chronic pain after surgery and, possibly, also nausea and vomiting. Therefore, the development of these more selective COX-2 inhibitors, in conjunction with preoperative patient selection, opens the way for their safer use in the perioperative period. The one area of real concern continues to be renal function, and until further evidence appears, any preoperative evidence of renal dysfunction should preclude their use. However, because selective COX-2 inhibitors are well tolerated by patients with asthma, are associated with less gastric injury (at least acutely), and do not influence hemostasis (43), they may represent a safer alternative to nonselective NSAIDs in the treatment of postoperative pain.
1. Ballantyne JC, Carr DB, DeFerranti S, et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized controlled trials. Anesth Analg 1998; 86: 598–612.
2. Harmer M, Davies KA. The effect of education, assessment and a standardised prescription on postoperative pain management. Anaesthesia 1998; 53: 424–30.
3. Carr DB, Goudas LC. Acute pain. Lancet 1999; 353: 2051–8.
4. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. Anesthesiology 2000; 93: 1123–33.
5. Pertunnen K, Kalso E, Heinonen J, Salo J. IV diclofenac in post-thoracotomy pain. Br J Anaesth 1992; 68: 474–80.
6. Morrison BW, Christensen S, Yuan W, et al. Analgesic effect of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized control trial. Clin Ther 1999; 21: 943–53.
7. Olofsson CI, Legeby MH, Nygårds F, Östman KM. Diclofenac in the treatment of pain after caesarean delivery: an opioid-saving strategy. Eur J Obstet Gynecol Reprod Biol 2000; 88: 143–6.
8. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231: 282–5.
9. Funk CD, Funk LB, Kennedy ME, et al. Human platelet/erythroleukaemia cell prostaglandin G/H synthase: cDNA cloning, expression and gene chromosomal assignment. FASEB J 1991; 5: 2304–12.
10. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A 1992; 89: 7384–8.
11. Smith WL. Prostanoid biosynthesis and mechanisms of action. Am J Physiol 1992; 263: 181–91.
12. Angel J, Berenbaum F, Le Denmat C, et al. Interleukein-1-induced prostaglandin E2 biosynthesis in human synovial cells involves the activation of cytosolic phospholipase A2 and cyclooxygenase-2. Eur J Biochem 1994; 226: 125–31.
13. Chepenik KP, Diaz A, Jimenez SA. Epidermal growth factor co-ordinately regulates the expression of prostaglandin G/H synthase and cytosolic phospholipase A2 genes in embryonic mouse cells. J Biol Chem 1994; 269: 21786–92.
14. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 1996; 271: 33157–60.
15. Okamoto T, Hino O. Expression of cyclooxygenase-1 and -2 mRNA in rat tissues: tissue-specific difference in the expression of the basal level of mRNA. Int J Mol Med 2000; 6: 455–7.
16. Ancian P, Lambeau G, Mattei MG, Lazdunski M. The human 180-kDa receptor for secretory phospholipases A2: molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization. J Biol Chem 1995; 270: 8963–70.
17. Willingale HL, Gardiner NJ, McLymont N, et al. Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. Br J Pharmacol 1997; 122: 1593–604.
18. Beiche F, Brune K, Geisslinger G, Goppelt-Struebe M. Expression of cyclooxygenase isoforms in the rat spinal cord and their regulation during adjuvant-induced arthritis. Inflamm Res 1998; 47: 482–7.
19. Bley KR, Hunter JC, Eglen RM, Smith JA. The role of IP prostanoid receptors in inflammatory pain. Trends Pharmacol Sci 1998; 19: 141–7.
20. Matsumura K, Watanabe Y, Onoe H, Watanabe Y. Prostacyclin receptor in the brain and central terminals of the primary sensory neurons: an autoradiographic study using a stable prostacyclin analogue [3
H] iloprost. Neuroscience 1995; 65: 493–503.
21. Ebersberger A, Grubb BD, Willingale HL, et al. The intraspinal release of prostaglandin E2 in a model of acute arthritis is accompanied by an up-regulation of cyclo-oxygenase-2 in the spinal cord. Neuroscience 1999; 93: 775–81.
22. Evans AR, Junger H, Southall MD, et al. Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons. J Pharmacol Exp Ther 2000; 293: 912–20.
23. Minami T, Du R, Horiguchi S, et al. Allodynia evoked by intrathecal administration of prostaglandin E2
to conscious mice. Pain 1994; 57: 217–23.
24. Zhao Z, Chen SR, Eisenach JC, et al. Spinal cyclooxygenase-2 is involved in development of allodynia after nerve injury in rats. Neuroscience 2000; 97: 743–8.
25. Beiche F, Scheuerer S, Brune K, et al. Upregulation of cyclooxygenase-2 mRNA in the rat spinal cord following inflammation. FEBS Lett 1996; 390: 165–9.
26. Goppelt-Strruebe M, Beiche F. Cyclooxygenase-2 in the spinal cord: localization and regulation after a peripheral inflammatory stimulus. Adv Exp Med Biol 1997; 433: 213–6.
27. Hay C, deBelleroche J. Carrageenan-induced hyperalgesia is associated with cyclooxygenase expression in the spinal cord. Neuroreport 1997; 8: 1249–51.
28. Pitcher GM, Henry JL. Mediation and modulation by eicosanoids of responses of spinal dorsal horn neurons to glutamate and substance P receptor agonists: results with indomethacin in the rat in vivo. Neuroscience 1999; 93: 1109–21.
29. Sejbert 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 U S A 1994; 91: 12013–7.
30. Kaufman WE, Worley PF, Pegg J, et al. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A 1996; 93: 2317–21.
31. Lerea LS, Carlson NG, Simonato M, et al. Prostaglandin F2a is required for NMDA receptor-mediated induction of c-fos mRNA indentate gyrus neurons. J Neurosci 1997; 17: 117–24.
32. Seeberg PH. The TIPPS/TINS lecture: the molecular biology of the mammalian glutamate receptor changes. Trends Pharmacol Sci 1993; 14: 297–303.
33. Thompson SW, Woolf C, Sivilotti LG. Small C-fibre afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibres in the neonatal rat spinal cord in vitro. J Neurophysiol 1993; 69: 2116–28.
34. Dickenson AH. Spinal cord pharmacology of pain. Br J Anaesth 1995; 75: 193–200.
35. Wiesenfeld-Hallin Z. Combined opioid-NMDA antagonist therapies: what advantages do they offer for the control of pain syndromes? Drugs 1998; 55: 1–4.
36. Dolan S, Nolan AM. N-methyl D-aspartate induced mechanical allodynia is blocked by nitric oxide synthase and cyclooxygenase-2 inhibitors. Neuroreport 1999; 10: 449–52.
37. Miettinen S, Fusco FR, Yrjanheikki J, et al. Spreading depression and focal brain ischaemia induce cyclooxygenase-2 in cortical neurons through NMDA receptors and phospholipase A2. Proc Natl Acad Sci U S A 1997; 94: 6500–5.
38. Koistinaho J, Koponen S, Chan PH. Expression of cyclooxygenase-2 mRNA after global ischaemia is regulated by AMPA receptors and glucocorticoids. Stroke 1999; 30: 1900–5.
39. Yamamoto T, Sakashita Y. COX-2 inhibitor prevents the development of hyperalgesia induced by intrathecal NMDA or AMPA. Neuroreport 1998; 9: 3869–73.
40. Beiche F, Klein T, Nusing R, et al. Localization of cyclooxygenase-2 and prostaglandin E2 receptor EP3 in the rat lumbar spinal cord. J Neuroimmunol 1998; 89: 26–34.
41. Basbaum AI. Spinal mechanisms of acute and chronic pain. Reg Anesth Pain Med 1999; 24: 59–67.
42. Basbaum AI. Distinct neurochemical features of acute and persistent pain. Proc Natl Acad Sci U S A 1999; 96: 7739–43.
43. Hawkey CJ. Cox-2 inhibitors. Lancet 1999; 353: 307–14.
44. Raskin JB. Gastrointestinal effects of nonsteroidal antiinflammatory drugs. Am J Med 1999; 106: 3S–12S
45. Hawkey CJ. Nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology 2000; 119: 521–35.
46. Iseki S. Immunohistological localization of cyclooxygenase-1 and cyclooxygenase-2 in the rat stomach. Histochem J 1995; 27: 323–8.
47. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997; 112: 387–97.
48. Shigeta J, Takahashi S, Okabe S. Role of cyclooxygenase-2 in the healing of gastric ulcers in rats. J Pharmacol Exp Ther 1998; 286: 1383–90.
49. Jones MK, Wang H, Peskar BM, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 1999; 5: 1418–23.
50. Warner TD, Giuliano F, Vojnovic I, et al. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A 1999; 96: 7563–8.
51. Langenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995; 83: 483–92.
52. Fu S, Ramanujam KS, Wong A, et al. Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase-2 in Helicobacter pylori
gastritis. Gastroenterology 1999; 116: 1319–29.
53. Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase-2 inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 1999; 117: 776–83.
54. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized control trial. JAMA 1999; 282: 1921–8.
55. Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 2000; 119: 706–14.
56. Wallace JL, Arfors KE, McKnight GW. A monoclonal antibody against the CD18 adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology 1991; 100: 878–83.
57. Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997; 112: 1000–16.
58. Dequeker J, Hawkey C, Kahan A, et al. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998; 37: 946–51.
59. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999; 354: 2106–11.
60. Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000; 95: 1681–90.
61. Hawkey C, Kahan A, Steinbruck K, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients: International MELISSA Study Group—Meloxicam Large-scale International Study Safety Assessment. Br J Rheumatol 1998; 37: 937–45.
62. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal side effects of rofecoxib compared with NSAIDs. JAMA 1999; 282: 1929–33.
63. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal 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 2000; 284: 1247–55.
64. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–8.
65. Alexopoulos E. Drug-induced acute interstitial nephritis. Ren Fail 1998; 20: 809–19.
66. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984; 310: 563–72.
67. Griffin MR, Yared A, Ray WA. Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 2000; 151: 488–96.
68. Hao CM, Komhoff M, Guan Y, et al. Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial survival. Am J Physiol 1999; 277: F352–9.
69. Eras J, Perazella MA. NSAIDs and the kidney revisited: are selective COX-2 inhibitors safe? Am J Med Sci 2001; 321: 181–90.
70. Harris RC. Macula densa signalling: a potential role for cyclooxygenase-2 (COX-2). Nephrol Dial Transplant 2000; 15: 1504–6.
71. Rodriguez F, Llinas MT, Gonzalez JD, et al. Renal changes induced by a cyclooxygenase-2 inhibitor in normal and low sodium intake. Hypertension 2000; 36: 276–81.
72. Wang JL, Cheng HF, Shappell S, Harris RC. A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats. Kidney Int 2000; 57: 2334–42.
73. Whelton A. Renal and related cardiovascular effects of conventional and COX-2-specific NSAIDs and non-NSAID analgesics. Am J Ther 2000; 7: 63–74.
74. Perazella MA. Drug-induced hyperkalemia: old culprits and new offenders. Am J Med 2000; 109: 307–14.
75. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, haemodynamics and vasoactive eicosanoids. J Pharmacol Exp Ther 1999; 289: 735–41.
76. Rossat J, Maillard M, Nussberger J, et al. Renal effects of selective COX-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 1999; 66: 76–84.
77. Whelton A, Brater DC, Sica DA, et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med 2000; 160: 1465–70.
78. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis 2000; 35: 937–40.
79. Whelton A, Fort JG, Puma JA, et al. Cyclooxygenase-2–specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001; 8: 85–95.
80. Rocha JL, Fernandez-Alonso J. Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 2001; 357: 1946–7.
81. Graham MG. Acute renal failure related to high-dose celecoxib. Ann Intern Med 2001; 135: 69–70.
82. Jaquenod M, Ronnhedh C, Cousins MJ, et al. Factors influencing ketorolac-associated perioperative renal dysfunction. Anesth Analg 1998; 86: 1090–7.
83. Kim H, Xu M, Lin Y, et al. Renal dysfunction associated with the perioperative use of diclofenac. Anesth Analg 1999; 89: 999–1005.
84. Scott CS, Retsch-Bogart GZ, Henry MM. Renal failure and vestibular toxicity in an adolescent with cystic fibrosis receiving gentamicin and standard-dose ibuprofen. Pediatr Pulmonol 2001; 31: 314–6.
85. Guo Y, Jones WK, Xuan YT, et al. The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci U S A 1999; 96: 10953–4.
86. LaPointe MC, Isenovic E. Interleukin-1 beta regulation of inducible nitric oxide synthase and cyclooxygenase-2 involves the p42/44 and p38 MAPK signalling pathways in cardiac myocytes. Hypertension 1999; 33: 276–82.
87. Shinmura K, Tang X, Wang Y, et al. Cyclooxygenase mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci U S A 2000; 97: 10197–202.
88. Farber NE, Gross GJ. Prostaglandin redirection by thromboxane synthetase in attenuation of myocardial stunning in canine heart. Circulation 1990; 81: 369–80.
89. Hide EJ, Ney P, Piper J, et al. Reduction by prostaglandin E1 or prostaglandin E0 of myocardial infarct size in the rabbit by activation of ATP-sensitive potassium channels. Br J Pharmacol 1995; 116: 2435–40.
90. Smalling RW, Feld S, Ramanna N, et al. Infarct salvage with prostaglandin E1 administered by intermittent bolus immediately before reperfusion in a canine infarction-reperfusion model. Circulation 1995; 92: 935–43.
91. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115–26.
92. Masferrer JL, Needleman P. Anti-inflammatories for cardiovascular disease. Proc Natl Acad Sci U S A 2000; 97: 12400–1.
93. Reis ED, Roque M, Dansky H, et al. Sulindac inhibits neointimal formation after arterial injury in wild-type and apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A 2000; 97: 12764–9.
94. Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxidases. Proc Natl Acad Sci U S A 1975; 72: 2994–8.
95. Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation. Prostaglandins 1976; 12: 897–913.
96. Stanke-Labesque F, Devillier P, Bedouch P, et al. Angiotensin 11-induced contractions in human internal mammary artery: effects of cyclooxygenase and lipoxygenase inhibition. Cardiovasc Res 2000; 47: 376–83.
97. Girod V, Bouvier M, Grelot L. Characterisation of lipopolysaccharide-induced emesis in conscious piglets: effects of cervical vagotomy, cyclooxygenase inhibitors and 5-HT(3) receptor antagonism. Neuropharmacology 2000; 39: 2329–35.
98. Crofford LJ, Oates JC, McCune WJ, et al. Thrombosis in patients with connective tissue diseases with specific cyclooxygenase 2 inhibitors: a report of four cases. Arthritis Rheum 2000; 43: 1891–6.
99. Okamoto H, Roman RJ, Kampine JP, Hudetz AG. Endotoxin augments cerebral hyperemic response to halothane by inducing nitric oxide synthase and cyclooxygenase. Anesth Analg 2000; 91: 896–903.
100. Grygleweski RJ. Aspirin induced asthma and cyclooxygenases. In: Vane J, Botting J, eds. Selective COX-2 inhibitors: pharmacology, clinical effects and therapeutic potential. Boston: Kluwer Academic, 1998: 99–107.
101. Babu KS, Salvi SS. Aspirin and asthma. Chest 2000; 118: 1470–6.
102. Bennett A. The importance of COX-2 inhibition for aspirin induced asthma. Thorax 2000; 55: S54–6.
103. Dahlen B, Szceklik A, Murray JJ. Celecoxib in patients with asthma and aspirin intolerance: the Celecoxib in Aspirin-Intolerant Asthma Study Group. N Engl J Med 2001; 344: 142.
104. Kissin I. Preemptive analgesia. Anesthesiology 2000; 93: 1138–43.
105. McCrory C, Diviney D, Moriarty J, et al. Spinal prostaglandin formation and pain perception following thoracotomy: a role for cyclooxygenase-2 [abstract]. Anesthesiology 2001; 95: A797.
106. Katz J. Pre-emptive analgesia: importance of timing. Can J Anesth 2001; 48: 105–14.
107. Norman PH, Daley MD, Lindsey RW. Preemptive analgesic effects of ketorolac in ankle fracture. Anesthesiology 2001; 94: 599–603.
108. O’Hanlon D, Thambipillai T, Colbert S, et al. Timing of pre-emptive tenoxicam is important for postoperative analgesia. Can J Anesth 2001; 48: 162–6.
109. McQuay HJ, Moore RA. Postoperative analgesia and vomiting, with special reference to daycase surgery: a systematic review. Health Technol Assess 1998; 2: 1–236.
110. Bensen WG. Antiinflammatory and analgesic efficacy of COX-2 specific inhibition: from investigational trials to clinical experience. J Rheumatol Suppl 2000; 60: 17–24.
111. Garnett WR. Clinical implications of drug interactions with coxibs. Pharmacotherapy 2001; 21: 1223–32.