Conventional non-steroidal anti-inflammatory drugs (NSAIDs), or non-specific cyclo-oxygenase (COX) inhibitors, have considerable efficacy in the management of pain and inflammation associated with rheumatoid arthritis (RA), osteoarthritis (OA) and other painful conditions . In addition, they have a major role in the treatment of acute pain, including pain after surgery [2-7]. However, because of COX-1 enzyme inhibition, these drugs are associated with a significant incidence rate of mortality and morbidity [8-10]. Gastrointestinal ulceration and bleeding are the most frequent serious complications of conventional NSAID use [11-13], but other side-effects include inhibition of platelet function and impairment of renal function in dehydrated or sodium-depleted patients [12,14-16]. Understandable safety concerns limit the use of conventional NSAIDs as agents in the management of pain in many patients.
COX-2-selective inhibitors are now available for oral administration. They maintain the therapeutic benefits of conventional NSAIDs [17-20], but are not associated with a poor adverse event profile due to their COX-1-sparing nature [21-24]. However, for the management of acute pain, there is a need for an injectable agent, which, in contrast to injectable NSAIDs such as ketorolac, is devoid of effects on the gastrointestinal mucosa and platelet function.
Two highly selective oral COX-2 inhibitors are currently available, celecoxib and rofecoxib [17-20]. A third, valdecoxib, has recently been approved in the USA and Europe. Parecoxib sodium, the injectable water-soluble prodrug of the novel COX-2-selective inhibitor valdecoxib, is currently in clinical development and has recently been approved in several European countries. This review will briefly describe the established clinical efficacy and safety of celecoxib as it relates to chronic pain management, and discuss the potential of parecoxib sodium as a new agent for the management of acute pain.
Structure of COX-2-selective inhibitors
NSAIDs are non-selective inhibitors of both COX-1 and COX-2, but their anti-inflammatory activity is mediated only by inhibition of COX-2 [25,26]. NSAIDs function by binding to and blocking the active site of COX. The substrate-binding site of the enzyme is within the catalytic domain in a pocket surrounded by three α-helices at the mouth of the channel, with charged amino acid residues at each turn in the helices (Fig. 1)[27,28]. Conventional NSAIDs have a common carboxylic or enolic acid group that facilitates binding to a charged arginine residue (Arg120) near the active site of the enzyme, thereby blocking substrate access to amino acid residues such as Tyr385 that are essential for catalysis [29,30]. The molecular structure of conventional NSAIDs is essentially linear and allows them access to the active site of both COX-1 and COX-2 isoforms (Fig. 1). While NSAIDs exert their therapeutic effects via inhibition of COX-2, their non-selective inhibition of COX-1 is responsible for the inhibition of platelet function and gastrointestinal complications characteristic of this class of drugs.
Single amino acid differences in the active sites of COX-1 and COX-2 account for the selectivity of COX-2-selective inhibitors, the most critical of which seems the substitution of the valine residue (Val509) in COX-2 for isoleucine in COX-1 [32,33]. In the COX-2 isoform, the valine residue, with its smaller side chain, makes a side pocket adjacent to the active site accessible to COX-2-selective inhibitors [31,34]. In contrast, the COX-1 substrate channel is much narrower owing to the presence of the larger isoleucine residue, and, therefore, it cannot accommodate the COX-2-selective inhibitors with their bulky side-chains. All COX-2-selective inhibitors developed have this characteristic three-ring structure that allows them selectively to inhibit COX-2. The relatively linear structure of conventional NSAIDs does not exclude their binding to either isoform of COX, hence their lack of selectivity. COX-2-selective inhibitors also have a sulphonamide residue that encourages binding to specific residues within the side pocket of COX-2. In addition to the bulky side-chain, and in contrast to conventional NSAIDs, COX-2-selective inhibitors do not have a carboxylic or enolic residue that binds Arg120, which further discourages binding to COX-1.
The selectivity has been confirmed by in vitro and in vivo animal experiments, and in clinical trials. In vitro enzyme activity assays have been useful in determining the structure-activity relationships of COX-2-selective inhibitors and have demonstrated greatly increased selectivity of COX-2-selective inhibitors [32,33,35]. Celecoxib demonstrates greater selectivity for COX-2 (IC50 = 0.004 μmol) compared with COX-1 (IC50 = 15 μmol) , as does the novel COX-2-selective inhibitor valdecoxib (IC50 = 0.005 μmol for COX-2 versus IC50 = 140 μmol for COX-1) . In vitro enzyme kinetic assays differ markedly depending on the assay system used, and despite being an indication of activity, in vitro assays may not accurately predict in vivo effects. However, in vivo models for inflammation, such as the carageenan air-pouch model in rats, have been developed and demonstrate the efficacy of COX-2-selective inhibitors [38-42]. This model consists of an air cavity produced by subcutaneous injection of air into the intracapsular area of the backs of rats. Following injection of air, anti-inflammatory drugs are administered orally and inflammatory agents such as carageenan are injected into the air pouch to produce an inflammatory response. High concentrations of prostaglandin derived from COX-2 activity are released into the air pouch. Additionally, concentrations of prostaglandins produced in the gastric mucosa of these animals can be measured simultaneously. The high selectivity of celecoxib and valdecoxib for COX-2 has been confirmed in such in vivo models.
Valdecoxib is a novel COX-2-selective inhibitor being developed for the treatment of acute pain and for the pain and inflammation associated with OA, RA and dysmenorrhea. In common with other COX-selective inhibitors, valdecoxib has a three-benzene ring structure with a sulphonamide group to facilitate binding into the side-pocket of the COX-2 catalytic domain (Fig. 2). Currently, valdecoxib is the only reported COX-2-selective inhibitor available as a water-soluble prodrug. Parecoxib sodium, the prodrug of valdecoxib, is available as an injectable formulation that can be administered intravenously (i.v.) and intramuscularly (i.m.) (Fig. 2). Parecoxib sodium reaches peak plasma concentration within 2.5 and ∼15 min following i.v. and i.m. administration, respectively, and is rapidly hydrolysed to its active form valdecoxib, which reaches peak plasma concentration within 30-60 or 80-150 min following i.v. or i.m. administration, respectively.
Efficacy and safety of currently available COX-2-selective inhibitors in RA and OA
Celecoxib is a COX-2-selective inhibitor currently available for the relief of the signs and symptoms of OA and RA. As a COX-2-selective agent, it is effective in managing both the pain and inflammation associated with these conditions.
Efficacy of celecoxib in chronic pain management
Pain is one of the main symptoms associated with both OA and RA [43,44], and the efficacy of celecoxib in these conditions has been described in many studies. The analgesic efficacy of celecoxib compared with conventional NSAID therapy (naproxen and diclofenac), in treating OA of the hip and knee, has been investigated in large, randomized, double-blind, placebo-controlled studies in adults with arthritis flare after discontinuation of conventional NSAID, and those with active RA [17,19,20,23]. The efficacy of celecoxib was equivalent to full therapeutic doses of the conventional NSAIDs studied.
In patients with OA of the hip or knee, celecoxib showed similar analgesic efficacy to diclofenac  and naproxen . In 2529 patients, celecoxib 100 mg b.i.d. (twice daily dosing; the approved dose for OA) reduced pain scores on the Western Ontario and McMaster's Universities Osteoarthritis Index (WOMAC)  and patient's assessment of pain by the visual analogue scale (VAS)  to the same extent as diclofenac or naproxen.
Two key studies have investigated the effects of celecoxib on pain-related outcomes compared with conventional NSAIDs in patients with RA. In a randomized, placebo-controlled study of more than 600 patients with RA, the efficacy of celecoxib was compared with diclofenac . Celecoxib was as effective as diclofenac with respect to the pain-related outcomes measure and the change in the number of painful or tender joints (average reduction of 5.8 with celecoxib and 5.3 with diclofenac) (Fig. 3). In addition, on the VAS pain score assessment, both treatments were equivalent (celecoxib treatment resulted in a VAS score reduction of 6.6 mm compared with an 8.6 mm reduction with diclofenac). In a separate 12 week, placebo-controlled study comparing celecoxib 200 mg b.i.d. (the maximum recommended dose for RA) with naproxen 500 mg b.i.d. in 1149 patients, the average reduction in the number of tender and painful joints in those treated with celecoxib 200 mg b.i.d. was 12.4 compared with 9.5 with naproxen and 7.6 with placebo . The reductions associated with celecoxib and naproxen were significant (P < 0.05) compared with placebo. A similar pattern was reported with respect to the number of swollen joints. These data suggest that celecoxib 200 mg b.i.d. is as effective in relieving joint pain and discomfort associated with OA and RA as naproxen 500 mg b.i.d. and diclofenac 75 mg b.i.d.
Safety of celecoxib in chronic pain management
The safety and tolerability of celecoxib has also been evaluated in clinical studies. The studies have demonstrated that COX-2-selective inhibitors do not affect the gastrointestinal mucosa or platelet function in any clinically meaningful manner, unlike the conventional NSAIDs used as comparators.
Gastrointestinal effects. The gastrointestinal safety of celecoxib was evaluated endoscopically as part of the clinical study programme using celecoxib 400 mg b.i.d. (two and four times the maximum clinically effective doses for RA and OA, respectively).
Studies among patients with arthritis have shown that the supratherapeutic doses of celecoxib investigated were associated with significantly fewer ulcers than the conventional NSAIDs used as comparators. The incidence of ulcers seen with celecoxib was similar to that seen with placebo [19,23].
Celecoxib 200 mg b.i.d. was compared with diclofenac 75 mg b.i.d. for 24 weeks in patients with adult-onset RA, of whom 430 were evaluable endoscopically . Gastroduodenal ulcers were detected in significantly more patients treated with diclofenac (15%) compared with celecoxib (4%) (P < 0.001) (Fig. 4). The ulcers were approximately twice the size in diclofenac-treated patients (average 1 cm diameter) compared with those in the celecoxib group (0.5 cm).
In other endoscopy studies comparing the incidence of ulcers with celecoxib and naproxen treatment, naproxen was consistently associated with significantly more gastrointestinal ulcers than celecoxib [21-23]. For example, in a 12 week, placebo-controlled study in 1149 adult patients with RA, the incidence rate of gastroduodenal ulcers was evaluated endoscopically at the end of treatment compared with baseline and it was significantly higher in the naproxen 500 mg b.i.d. group (26%) than with even the highest dose (400 mg b.i.d.) of celecoxib (6%) (P < 0.001). Celecoxib treatment at any dose did not result in more gastroduodenal ulcers than placebo. Additionally, in a serial endoscopy study (endoscopy assessment after 4, 8 and 12 weeks of therapy) of celecoxib and naproxen in patients with either RA or OA, the cumulative incidence of ulcers was significantly higher after 12 weeks of naproxen 500 mg b.i.d. than with celecoxib 200 mg b.i.d. (48 versus 9%, P < 0.001) . Furthermore, in a long-term arthritis safety trial, supratherapeutic doses of celecoxib were associated with a lower incidence of symptomatic ulcers and ulcer complications combined compared with standard doses of NSAIDs .
Thus, although the efficacy of celecoxib and conventional NSAIDs is equivalent, there is a significant difference in the incidence of gastrointestinal ulceration in favour of celecoxib.
Platelet effects. COX-1, which plays an important role in platelet aggregation, is the only variant of the two COX isoenzymes expressed in platelets . Thus, platelet aggregation in patients given conventional NSAIDs can be disrupted , leading to the risk of prolonged bleeding. The effects of a supratherapeutic dose of celecoxib (600 mg b.i.d.) and a standard naproxen dose (500 mg b.i.d.) on platelet function were compared with placebo in a randomized, double-blind, placebo-controlled study in 24 healthy adults over 10 days . Platelet aggregation was assessed, ex vivo, at baseline on days 1 and 10 after the first dose of the study drug. Celecoxib treatment was equivalent to placebo, whereas naproxen produced statistically significant (P < 0.05) decreases in platelet aggregation compared with both placebo and celecoxib. This change with naproxen was evident by day 1, i.e., after the first dose, and was sustained over the study period (Fig. 5). Furthermore, patients who received naproxen demonstrated a significantly longer bleeding time compared with patients receiving celecoxib or placebo. There was no difference between celecoxib and placebo in terms of bleeding time (Fig. 5).
Parecoxib sodium is the water-soluble prodrug of the COX-2-selective inhibitor valdecoxib and is being developed as an injectable analgesic. The prodrug itself has no pharmacologic activity, but it is rapidly metabolized to the active drug after i.m. or i.v. injection (Fig. 2).
Efficacy of parecoxib sodium in managing acute pain in different surgical pain models
The efficacy of parecoxib sodium in managing acute pain following surgery was examined in several different surgical models including dental surgery, orthopaedic surgery and general surgical models. In all studies, parecoxib sodium demonstrated analgesic efficacy superior to placebo and similar to the parenteral NSAID ketorolac.
Oral surgery. In a randomized, double-blind, placebo-controlled study, 457 patients undergoing oral surgery (moderate to severe pain after third molar surgery) received increasing i.v. doses of parecoxib sodium 1, 2, 5, 10, 20, 50 and 100 mg placebo i.v. or ketorolac 30 mg i.v. Most tested doses of parecoxib sodium provided analgesic efficacy that was statistically significantly superior to placebo, as demonstrated by significantly improved time-weighted sum of pain relief (TOTPAR), sum of pain intensity difference (SPID) at 12 h (Table 1) and time-specific pain relief (Fig. 6) following administration of study medication. Parecoxib sodium (20-100 mg i.v.) also provided a rapid onset of action (within 15 min) that was significantly better than placebo (P < 0.05) (Table 1). Parecoxib sodium 20, 50 and 100 mg i.v. provided pain relief similar in terms of onset and magnitude to the active comparator ketorolac (Table 1 and Fig. 6). Additionally, the two higher doses of parecoxib sodium provided a longer duration of action compared with ketorolac (Fig. 6).
Orthopaedic surgery. The analgesic efficacy of parecoxib was superior to that of a single small dose of morphine (4 mg) and equivalent to ketorolac in patients who had undergone total-knee arthroplasty. In this randomized, double-blind, placebo-controlled trial, the efficacy of single doses of parecoxib sodium 20 and 40 mg i.v. were compared with morphine 4 mg i.v., ketorolac 30 mg i.v. and placebo in 208 patients. Parecoxib sodium 40 mg i.v., ketorolac 30 mg i.v., and morphine 4 mg i.v. had similar median times to the onset of analgesia (Table 2). The time to onset of analgesia experienced by patients following parecoxib sodium 40 mg treatment was significantly shorter than for patients receiving parecoxib sodium 20 mg . Parecoxib sodium 40 mg and ketorolac also provided pain relief equivalent in terms of magnitude, with similar reductions in mean SPID scores from baseline to 12 h postdose. Additionally, patients receiving parecoxib sodium 40 mg experienced a significantly greater reduction in pain intensity than those receiving morphine or placebo (P < 0.05). The duration of action of single doses of parecoxib sodium and ketorolac was significantly better than for a single dose of morphine. Patients receiving parecoxib sodium 20 or 40 mg or ketorolac had a significantly longer median time to rescue medication than those receiving morphine or placebo (Table 2).
General surgery. In a general surgery model, parecoxib sodium demonstrated equivalent efficacy to ketorolac and superior efficacy to morphine 4 mg i.v. In this randomized, double-blind, placebo-controlled trial, the efficacy of single doses of parecoxib sodium 20 and 40 mg i.v. were compared with morphine 4 mg i.v., ketorolac 30 mg i.v. or placebo in 202 women who had undergone total abdominal hysterectomy or myomectomy . All active treatments resulted in a rapid onset of action that was significantly better than placebo (Table 3). Parecoxib sodium 20 and 40 mg i.v. and ketorolac 30 mg i.v. provided superior analgesic efficacy to morphine 4 mg i.v. and placebo, with the mean SPID scores increasing significantly over 12 h (P < 0.05) (Table 3). The mean scores for patients treated with morphine 4 mg i.v. increased but were not significantly different compared with placebo . The median time to the rescue medication for patients who received parecoxib sodium 20 or 40 mg i.v. or ketorolac 30 mg i.v. ranged from 6 to 6.5 h, and was significantly longer than the median time to rescue medication for placebo or morphine 4 mg i.v. treatment.
Safety of parecoxib sodium
Platelet safety. Inhibition of platelet aggregation and prolonged bleeding are among the most common side-effects observed with conventional NSAID treatment. The platelet aggregation effects of parecoxib sodium have been evaluated in two double-blind, randomized studies in both healthy elderly and non-elderly subjects . Parecoxib sodium 40 mg b.i.d. i.v. was compared with i.v. ketorolac 15 mg q.i.d. (four times daily) in subjects who were ≥65 years, or 30 mg q.i.d. in adult subjects ≤55 years for 8 days. Parecoxib sodium had little or no effect on platelet aggregation compared with placebo in healthy elderly subjects. In contrast, ketorolac treatment significantly decreased (P < 0.001) platelet aggregation compared with placebo and parecoxib sodium (Fig. 7).
Inhibition of platelet aggregation resulting from inhibition of COX-1 in platelets by conventional NSAIDs is an important consideration as this may lead to prolonged bleeding. This is of particular concern in some surgical procedures as it may enhance the risk of bleeding complications and, therefore, may prohibit the pre- and intraoperative administration of conventional NSAIDs. Parecoxib sodium had no significant effect on bleeding time in healthy adult subjects compared with placebo. In contrast, administration of ketorolac 30 mg i.v. for 8 days caused a significant increase in bleeding time compared with both placebo and parecoxib sodium 40 mg i.v. in non-elderly subjects (Fig. 8).
Gastrointestinal safety. The gastrointestinal safety of parecoxib sodium similarly has been assessed endoscopically in healthy elderly subjects in two randomized, double-blind, placebo-controlled studies. In one 7 day study, i.v. parecoxib sodium 40 mg b.i.d. was compared with i.v. ketorolac 15 mg q.i.d. in 94 patients . This study was conducted in the USA where ketorolac treatment is restricted to a maximum of 5 days . As a result, patients randomized to the ketorolac group received placebo for the first 2 days of the study. At the end of the study, no patients in either the placebo or parecoxib sodium groups had gastroduodenal ulcers compared with 23% of patients who received ketorolac (Fig. 9).
The second parecoxib sodium safety study compared i.v. parecoxib sodium 10 mg b.i.d. and oral naproxen 500 mg b.i.d. (both for 7 days), i.v. ketorolac 15 mg q.i.d. (5 days) and placebo (7 days) . All patients receiving ketorolac had ulcers at the end of the study compared with 50% of those in the naproxen group, none of those in the parecoxib sodium group and 40% of those who received placebo .
There is now a wealth of data demonstrating the efficacy of COX-2-selective inhibitors for the treatment of chronic pain and the inflammation associated with OA and RA. Thus, COX-2-selective inhibitors such as celecoxib have been demonstrated to be as effective as the conventional NSAIDs diclofenac and naproxen. Furthermore, COX-2-selective inhibitors are far less likely to be associated with upper gastrointestinal ulceration, perforation and bleeding.
Parecoxib sodium is a novel parenteral prodrug formulation of the COX-2-selective inhibitor valdecoxib. The oral COX-2-selective inhibitors rofecoxib and celecoxib are associated with opioid-sparing effects and effective pain relief in postoperative surgical patients . However, the use of a water-soluble preparation such as parecoxib in this situation has clear and definite advantages.
Ketorolac is the only parenteral conventional NSAID currently available in the USA, and although it is an effective analgesic, it is associated with an array of adverse effects including decreased platelet aggregation, increased bleeding time, gastrointestinal ulceration and bleeding, and acute renal failure [15,58-60]. In fact, it is recommended in the USA that prescription of ketorolac should be limited to 5 days due to the severity of gastrointestinal bleeding and adverse effects that can arise with its use . Other conventional NSAIDs, e.g., diclofenac and the analgesic acetaminophen (paracetamol), are available in parenteral formulations in Europe [4,5,62]. However, all conventional NSAIDs are associated with inhibition of platelet function and gastrointestinal ulceration and, therefore, should be used with caution when they are administered to surgical patients .
There is a general reluctance to use conventional NSAIDs perioperatively, even for relatively minor procedures such as oral surgery, because of the increased bleeding risks they pose [59,64]. Therefore, there is a need for parenteral analgesic agents that can be administered to surgical patients without the risk of increased bleeding. An injectable COX-2-selective inhibitor that provides strong analgesic efficacy with an improved side-effect profile compared with conventional NSAIDs would fulfil such a role.
Parecoxib sodium has demonstrated excellent clinical efficacy in a variety of different surgical models. Thus, a 40 mg dose of parecoxib sodium provides efficacy at least equivalent in terms of onset and magnitude to the parenteral conventional NSAID ketorolac in managing pain following surgery in oral, orthopaedic and general surgical models [50-52]. Furthermore, in some models, parecoxib sodium 40 mg provides a longer duration of action than ketorolac. Single doses of parecoxib sodium are more effective in treating postoperative pain than a single, small (4 mg i.v.) dose of morphine following orthopaedic and general surgery, as demonstrated by a greater magnitude of pain relief and a longer duration of action [51,52].
Consistent with the COX-1-sparing nature of COX-2-selective inhibitors, parecoxib sodium has no statistically significant effect on platelet aggregation or bleeding time compared with placebo. This lack of effect on platelet function is of distinct benefit in surgical populations at risk from bleeding complications. Unlike conventional NSAIDs, the lack of platelet inhibition associated with parecoxib sodium suggests that it could be administered perioperatively without the risk of increased bleeding complications. COX-2 is induced both at the sites of surgical incision and in the CNS during surgery. Therefore, it is hypothesized that pre- and intraoperative administration of a COX-2-selective inhibitor would allow sufficient time for the onset of analgesia, through inhibition of COX-2, before the effects of the anaesthesia wear off. Parecoxib sodium, an effective, injectable COX-2-selective inhibitor that does not cause bleeding complications normally associated with conventional NSAIDs, might be suitable for such applications.
1. Brooks PM, Day RO. Nonsteroidal anti-inflammatory drug differences and similarities. N Engl J Med
2. Buggy DJ, Wall C, Carton EG. Preoperative or postoperative diclofenac for laparoscopic tubal ligation. Br J Anaesth
3. 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
4. Hovorka J, Kallela H, Korttila K. Effect of intravenous diclofenac on pain and recovery profile after day-case laparoscopy. Eur J Anaesthesiol
5. Rosenblum M, Weller RS, Conrad PL, et al.
Ibuprofen provides longer lasting analgesia than fentanyl after laproscopic surgery. Anesth Analg
6. 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
7. Walton GM, Rood JP, Snowdon AT, et al.
Ketorolac and diclofenac for postoperative pain relief following oral surgery. Br J Oral Maxillofacial Surg
8. Blower AL, Brooks A, Fenn GC, et al.
Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther
9. Roth SH. A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis. Int J Tissue React
10. Roth SH. NSAID gastropathy. A new understanding. Arch Intern Med
11. Singh G, Ramey DR, Morfeld D, et al.
Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med
12. Vane JR, Botting RM. Mechanism of action of aspirin-like drugs. Sem Arthritis Rheumatism
1999; 26 (Suppl 1):
13. Verburg KM, Maziasz TJ, Weiner E, et al.
COX-2-specific inhibitors: definition of a new therapeutic concept. Am J Ther
14. Schror K. Aspirin and platelets: the antiplatelet action of aspirin and thrombosis treatement and prophylaxis. Sem Thrombosis Hemostasis
15. 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
16. Kenny GN. Potential renal, haematological and allergic adverse effects associated with non-steroidal anti-inflammatory drugs. Drugs
1992; 44 (Suppl 5):
17. Bensen WG, Fiechtner JJ, McMillen JI, et al.
Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc
18. 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
19. Emery P, Zeidler H, Kvien TK, et al.
Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: a randomised double-blind comparison. Lancet
20. McKenna F, Borenstein D, Wendt H, et al.
Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol
21. Bensen WG, Zhao SZ, Burke TA, et al.
Upper gastrointestinal tolerability of celecoxib, a COX-2-specific inhibitor, compared to naproxen and placebo. J Rheumatol
22. 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
23. Simon LS, Weaver AL, Graham DY, et al.
Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA
24. Watson DJ, Harper SE, Zhao PL, et al.
Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med
25. Laneuville O, Breuer DK, Dewitt DL, et al.
Differential inhibition of human prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther
26. Cryer B, Feldman H, Agrawal N. Cyclooxygenase-1 ancyclooxygenase-2 selectivity of widely used non-steroidal anti-inflammatory drugs. Am J Med
27. Garavito RM. The three dimensional structure of cyclooxygenases. In: Vane JR, Botting J, Botting R, eds. Improved Non-Steroidal Anti-Inflammatory Drugs: COX-2 Enzyme Inhibitors.
Dordrecht, Germany: Kluwer, 1996: 29-43.
28. Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase. Nature
29. Loll PJ, Picot D, Ekabo O, et al.
Synthesis and use of iodinated nonsteroidal anti-inflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site. Biochemistry
30. Mancini JA, Riendeau D, Falgueyret JP, et al.
Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by non-steroidal anti-inflammatory drugs containing a carboxylic acid moiety. J Biol Chem
31. Kurumbail RG, Stevens AM, Gierse JK, et al.
Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature
32. Gierse JK, McDonald JJ, Hauser SD, et al.
A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2-specific inhibitors. J Biol Chem
33. Gierse JK, Koboldt CM, Walker MC, et al.
Kinetic basis for selective inhibition of cyclo-oxygenases. Biochem J
34. Luong C, Miller A, Barnett J, et al.
Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat Struct Biol
35. Vane JR, Botting J. Overview mechanisms of action of anti-inflammatory drugs. In: Vane JR, Botting J, Botting R, eds. Improved Nonsteroidal Anti-inflammatory Drugs: COX-2 Enzyme Inhibitors.
Boston, USA. Kluwer, 1996: 1-27
36. Penning TD, Talley JJ, Bertenshaw SR, et al.
Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). J Med Chem
37. Talley JJ, Brown DL, Carter JS, et al.
4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem
38. Beiche F, Scheuerer S, Brune K, et al.
Up-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett
39. Hay C, de Belleroche J. Carrageenan-induced hyperalgesia is associated with increased cyclooxygenase-2 expression in spinal cord. Neuroreport
40. 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
41. Masferrer JL, Zweifel BS, Manning PT, et al.
Selective inhibition of inducible cyclooxygenase 2 in vivo
is anti-inflammatory and nonulcerogenic. Proc Natl Acad Sci USA
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. Creamer P, Hochberg M. Osteoarthritis. Lancet
44. Grassi W, DeAngelis R, Lamanna G, et al.
The clinical features of rheumatoid arthritis. Eur J Radiol
1998; 27 (Suppl 1):
45. Bellamy N. WOMAC Osteoarthritis Index: A User's Guide.
London, Canada: The Western Ontario and McMaster's Universities, 1995.
46. Cooperating Clinics Committee of American Rheumatism Association. A seven-day variability study of 499 patients with peripheral rheumatoid arthritis. Arthr Rheum
47. Patrignani P, Sciulli M, Manarini S. COX-2 is not involved in thromboxane biosynthesis by activated human platelets. J Physiol Pharmacol
48. Cronberg S, Wallmark E, Soderberg I. Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scand J Haematol
49. 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
50. Daniels S, Kuss M, Mehlisch D, et al.
Pharmacokinetic and efficacy evaluation of intravenous parecoxib in a postsurgical dental pain model [Abstract PIII-8]. Gastroenterology
51. Rasmussen GL, Steckner K, Hogue C, et al.
Intravenous parecoxib sodium for acute pain after postorthopedic knee surgery. Am J Orthop
52. Barton SF, Langeland FF, Snabes MC, et al.
Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following orthopedic surgery. Anesthesiology
53. Noveck RJ, Laurent A, Kuss M, et al.
The COX-2-specific inhibitor, parecoxib sodium, does not impair platelet function in healthy elderly and nonelderly subjects: two randomized, controlled trials. Clin Drug Invest
54. Stoltz R, Harris S, Kuss M, et al.
Upper gastrointestinal safety of parecoxib sodium in the elderly. Am J Gastroenterol
55. Syntex Laboratories I. Ketorolac prescribing information. Nutley, USA. Roche.
56. Harris S, Kuss M, Hubbard RC, et al.
Upper gastrointestinal tolerability evaluation of parecoxib sodium, a new parenteral COX-2-specific inhibitor, as compared to ketorolac, naproxen or placebo. Clin Ther
57. Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg
58. Choo V, Lewis S. Ketorolac doses reduced. Lancet
59. Spowart K, Greer IA, McLaren M, et al.
Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers. Thromb Haemost
60. Strom BL, Berlin JA, Kinman JL, et al.
Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA
61. Ketorolac (package insert). Nutley, USA. Roche, 2001.
62. Cooper SA, Precheur H, Rauch D, et al.
Evaluation of oxycodone and acetaminophen in treatment of postoperative dental pain. Oral Surg Oral Med Oral Pathol
63. Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective NL 1997 Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol
1998; 51 (Suppl):
64. Moote C. Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain. Drugs
1992; 44 (Suppl 5):
14-29, discussion 29-30.