Effects of nonsteroidal anti-inflammatory drugs on the expression of urokinase plasminogen activator and inhibitor and gelatinases in the early osteoarthritic knee of humans

OBJECTIVES: The purpose of this study was to examine the ex vivo effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the expression of urokinase-type plasminogen activator (u-PA), PA inhibitor-1 (PAI-1) and gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] in the early knee osteoarthritis (OA) of humans. DESIGN AND METHODS: Samples of articular cartilage, meniscus and synovium of OA patients were obtained and cultured ex vivo in the presence or absence of NSAIDs (diclofenac sodium, nimesulide, celecoxib, valdecoxib, rofecoxib and etoricoxib). RESULTS: Gelatin zymography showed that all NSAIDs generally decreased MMP-2 secretion in chondral, meniscal and synovial cultures as well as MMP-9 production in meniscal and synovial cultures. ELISA showed the inhibitions of u-PA secretion in chondral cultures by diclofenac and rofecoxib as well as in chondral and synovial cultures by nimesulide, celecoxib and etoricoxib at 48 h. On PAI-1 secretion, rofecoxib in synovial cultures and diclofenac, nimesulide, celecoxib and etoricoxib in chondral and synovial cultures had significantly suppressive effects at 48 h. CONCLUSIONS: This study clearly demonstrates that NSAIDs can down-regulate the PA/plasmin system and gelatinases expression during the early stage of knee OA, thereby possibly affect the structural progression of the disease. This inhibition seems to be independent selection of COX-1 and COX-2.     

Relative efficacy of selective COX-2 inhibitors compared with over-the-counter ibuprofen

Non-steroidal anti-inflammatory drugs (NSAIDs) suppress the activity of both isoforms of cyclo-oxygenase (COX). Inhibition of COX-1, the constitutive isoform, is primarily responsible for the adverse gastrointestinal effects of the NSAIDs whereas inhibition of COX-2, the inducible isoform, accounts for their therapeutic effects. COX-2 inhibitors such as celecoxib and rofecoxib appear to be as effective as non-selective NSAIDs in the treatment of chronic inflammatory disease but their analgesic efficacy and their safety at the higher doses required for analgesia are less certain. There is consistent evidence that COX-1 plays a major role in the early pain response following injury and that analgesia is increased when both COX-1 and COX-2 are inhibited simultaneously. Early postoperative nociception may cause hyperalgesia at a later time by a process of central plasticity. In an experimental model of pain, ibuprofen promptly suppresses prostaglandin E2 concentrations whereas celecoxib has no discernible effect until 90-120 minutes postoperatively, when COX-2 activity is induced. Both drugs significantly reduce pain compared with placebo but celecoxib appears to have a slower onset of action. The analgesic effect of ibuprofen is well characterised for acute pain and short-term treatment is well tolerated.     

The role of rofecoxib, a cyclooxygenase-2-specific inhibitor, for the treatment of non-cancer pain: a review.

Rofecoxib was the first specific inhibitor of cyclooxygenase-2 (COX-2) approved for the treatment of acute pain. It has been shown to provide analgesia that is significantly better than placebo and has an onset of action and efficacy similar to that of traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen and ibuprofen. In addition, the analgesic efficacy of rofecoxib has been demonstrated to be superior to that of the opioid combination of codeine 60 mg/acetaminophen 600 mg in an acute dental pain model. For the treatment of acute pain, the efficacy of rofecoxib was further demonstrated in a study of patients who had undergone orthopedic surgery. Rofecoxib has been found to be as effective as naproxen sodium and more effective than placebo in studies evaluating its use for the treatment of primary dysmenorrhea. In patients with osteoarthritis (OA) of the knee or hip, rofecoxib is superior to placebo and similar to diclofenac and ibuprofen in relieving OA pain and improving physical function. Rofecoxib has also been shown to be superior to acetaminophen and celecoxib after 6 weeks of treatment for OA. The efficacy of rofecoxib has also been demonstrated in patients with rheumatoid arthritis and low back pain. The advantages of using COX-2-specific NSAIDs include convenient once-daily dosing schedule and improved safety compared with traditional NSAIDs. Two large outcomes studies, VIGOR and CLASS, have shown that gastric mucosal ulceration occurs significantly less often in patients taking COX-2-specific inhibitors than in those treated with ibuprofen, diclofenac, or naproxen and occurs with a similar incidence to that of placebo. Absence of any effect on platelet aggregation and bleeding time further distinguishes these agents from traditional NSAIDs. Because COX-2-specific inhibitors do not have an antiplatelet effect, they cannot be used as a substitute for low-dose aspirin for cardiovascular prophylaxis. Rofecoxib is a safe and highly effective alternative to previously available NSAIDs and should be considered for the treatment of acute pain conditions in adult patients, especially those at risk for developing gastrointestinal complications. It is preferred in the perioperative setting because of its analgesic efficacy and lack of platelet effects. Because of its more favorable gastrointestinal toxicity profile compared with nonselective NSAIDs, rofecoxib is safer in patients, especially older patients, for whom chronic anti-inflammatory or analgesic therapy is indicated.     

Effects of nimesulide on pain and on synovial fluid concentrations of substance P, interleukin-6 and interleukin-8 in patients with knee osteoarthritis: comparison with celecoxib

OBJECTIVE: This study was designed to investigate the analgesic effects of nimesulide and celecoxib in patients with knee osteoarthritis (OA). In patients with joint effusion, the effects of these non-steroidal anti-inflammatory drugs (NSAIDs) on synovial fluid concentrations of substance P (SP), interleukin (IL)-6 and IL-8 also were evaluated. METHODS: Patients were randomly assigned either nimesulide (100 mg twice a day) or celecoxib (200 mg once a day) for 2 weeks. The intensity of joint pain was assessed with a 100-mm visual analogue scale (VAS). Furthermore, patients completed questions about analgesic efficacy and overall tolerability of the treatments on a five-point categorical scale. Synovial fluid samples were drawn at baseline, 30 min after the first drug intake (day 1), and 30 min after the last drug intake (day 14). RESULTS: We enrolled 44 patients, 20 of whom had a joint effusion. In this group, the effects of nimesulide were more marked than for celecoxib, with evidence of a faster onset of the analgesic action. Both after a single or repeated administration, nimesulide significantly reduced the synovial fluid concentrations of SP and IL-6. Celecoxib, on the other hand, did not change the concentrations of SP and significantly reduced the levels of IL-6 only on day 14. None of the drugs affected IL-8. Both drugs were generally well tolerated. CONCLUSIONS: These results provide evidence that nimesulide is an effective agent for the symptomatic treatment of OA. The effect on inflammatory pain mediators is consistent with the fast analgesic action of this NSAID.     

Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs: a case/noncase analysis of spontaneous reports

BACKGROUND: Hepatic adverse events associated with the use of nonaspirin drugs and NSAIDs are uncommon, but the widespread use of these drugs may impact public health. OBJECTIVE: We conducted a case/noncase analysis of spontaneous reports to compare the hepatic safety profile of cyclooxygenase (COX)-2 selective inhibitors with that of nonselective NSAIDs. METHODS: This case/noncase analysis was conducted using the US Food and Drug Administration Freedom of Information (FDA/FOI) database (through quarter 1, 2003) and the World Health Organization Uppsala Monitoring Centre (WHO/UMC) database (through quarter 3, 2003). Council for International Organizations of Medical Sciences and WHO Adverse Reaction Terminology preferred terms were used to classify hepatic disorders with broad and specific case definitions. After reports involving established hepatotoxic drugs (bromfenac, nimesulide, sulindac) were excluded, the proportion of reports (PRs) of each case definition was calculated for each NSAID. Crude and adjusted reporting odds ratios (RORs) were used to compare the overall proportions of hepatic disorders and hepatic failure of celecoxib and rofecoxib versus nonselective NSAIDs. RESULTS: A total of 158,539 and 185,253 reports of NSAIDs were identified in the FDA/FOI and WHO/UMC databases and 25% and 16%, respectively, involved other hepatotoxic drugs. The PRs of hepatic disorders for all COX-2 selective inhibitors and non-selective NSAIDs were 3.0% in the FDA/FOI database and 2.7% in the WHO/UMC database. In the FDA/FOI and WHO/UMC databases, respectively, mmesulide (16.7% and 14.4%), bromfenac (12.0% and 20.7%), diclofenac (8.1% and 4.7%), and sulindac (6.1 % and 9.9%) were reported to be associated with higher proportions of overall hepatic disorders compared with those of other NSAIDs. Crude and adjusted RORs for the prevalences of overall hepatic disorders and hepatic failure with celecoxib and rofecoxib versus the other NSAIDs were <1 (indicating that the proportion was not higher than that of the comparator) in both databases. The interpretation of the results was unchanged when bromfenac, nimesulide, and sulindac were excluded from the analysis. CONCLUSIONS: In this case/noncase analysis, bromfenac, nimesulide, sulindac, and diclofenac had higher proportions of reports of hepatic disorders compared with those of other NSAIDs in the FDA/FOI and WHO/UMC databases. The analysis did not raise a safety concern for celecoxib or rofecoxib versus NSAIDs for overall hepatic disorders and hepatic failure.     

ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor

Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED(50) of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis.     

Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial

Pain is a common complaint, often occurring in conjunction with inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesic agents in ambulatory patients. In recent studies, the cyclooxygenase-2 (COX-2) inhibitor rofecoxib demonstrated analgesic effects similar to those of NSAIDs in the treatment of acute pain and primary dysmenorrhea. The present randomized, single-dose, double-blind, double-dummy, placebo- and active-comparator-controlled, parallel-group study was undertaken to compare the analgesic efficacy of the COX-2 inhibitors rofecoxib 50 mg and celecoxib 200 mg with that of ibuprofen 400 mg and placebo in patients with postoperative dental pain. Two hundred and seventy-two patients experiencing pain after the removal of > or =2 third molars were randomized according to pain severity (moderate vs severe) to receive a single dose of placebo (n = 45), rofecoxib 50 mg (n = 90), celecoxib 200 mg (n = 91), or ibuprofen 400 mg (n = 46). Using a patient diary, patients recorded pain intensity, pain relief, and global evaluations throughout the 24-hour period after dosing. The overall analgesic effect, onset of action, peak effect, and duration of effect were evaluated, with the primary end point being total pain relief over 8 hours (TOPAR8). The safety profile was assessed on the basis of physical findings, laboratory results, and spontaneous reports of adverse experiences. The results showed that compared with celecoxib, rofecoxib had superior analgesic effects on all measures of analgesic efficacy, including overall analgesic effect (TOPAR8, 18.3 vs. 12.5; P<0.001), time to onset of effect (30 vs. 60 minutes; P = 0.003), peak pain relief (score, 2.8 vs 2.3; P<0.05), and duration of effect (>24 vs. 5.1 hours; P<0.001). In addition, rofecoxib's analgesic efficacy was similar to that of ibuprofen (TOPAR8, 18.3 vs. 17.0; P = 0.460), but the duration was longer (P<0.05); with ibuprofen, the time to on set was 24 minutes, peak pain relief score was 2.9, and duration of analgesic effect was 8.9 hours. The safety profile was similar across all treatment groups. Thus rofecoxib provided analgesic efficacy superior to that of celecoxib and comparable to that of ibuprofen in the treatment of patients with acute postoperative dental pain.     

Systematic review of the analgesic efficacy and tolerability of COX-2 inhibitors in post-operative pain control

OBJECTIVE: To evaluate the relative analgesic efficacy and tolerability of single-dose COX-2 inhibitors in post-operative pain management. METHOD: Systematic review of randomized controlled trials (RCTs). OUTCOME MEASURES: The area under the pain relief vs. time curve was used to evaluate the proportion of patient achieving at least 50% pain relief using validated equations. The proportions of patients experiencing any adverse event or specific adverse events were also examined. RESULTS: In all, 18 RCTs were included which contained 2783 patients. The results of the effects of single-dose analgesics on the basis of 50% of patients achieving pain relief over 6 h from dental pain models suggested that oral rofecoxib 50 mg was more effective than codeine/paracetamol 60/600 mg, and the rate ratio (RR) was 2.11 (95% CI 1.6-2.75). Valdecoxib 40 mg was also more effective than oxycodone/paracetamol 10/1000 mg (RR 1.34; 95% CI 1.11-1.62). There was no significant differences between other oral COX-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs), except that celecoxib 200 mg was less effective than ibuprofen 400 mg (RR 0.66; 95% CI 0.48-0.90) and rofecoxib 50 mg (RR 0.65; 95% CI 0.49-0.87). The results from orthopaedic pain model showed no significant difference between rofecoxib 50 mg and naproxen sodium 550 mg (RR 1.04; 95% CI 0.73-1.49). The adverse effects of single-dose COX-2 inhibitor used in short-term post-operative pain management were generally mild and less than non-selective NSAIDs, although there was no significant difference. CONCLUSIONS: The analgesic efficacy and tolerability of single-dose COX-2 inhibitors were more effective than opioid-containing analgesics and similar to non-selective NSAIDs in post-operative pain management. Further studies are needed to examine the efficacy and tolerability of COX-2 inhibitors compared against active comparators over a longer duration to assess whether these short-term effects are mirrored by longer-term outcomes and to determine their ultimate risk-benefit profile.     

Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat

The aim of the present study was to investigate the effects of cannabinoid agonists on established inflammatory hyperalgesia. We have compared the effects of pre-administration versus post-administration of a potent non-selective cannabinoid agonist HU210 and a selective CB2 receptor agonist JWH-133 on hindpaw weight bearing and paw oedema in the carrageenan model of inflammatory hyperalgesia. For comparative purposes we also determined the effects of the mu-opioid receptor agonist morphine and the COX2 inhibitor rofecoxib in this model. At 3 h following intraplantar injection of carrageenan (2%, 100 microl) there was a significant (P < 0.001) reduction in weight bearing on the ipsilateral hindpaw, compared to vehicle treated rats and a concomitant increase in ipsilateral hindpaw volume (P < 0.001), compared to vehicle treated rats. Systemic administration of HU210 (10 microg/kg) and JWH-133 (10 mg/kg) at 3 h following injection of carrageenan, significantly attenuated decreases in ipsilateral hindpaw weight bearing (P < 0.05 for both) and paw volume (P < 0.001 for both). Pre-administration of HU210 and JWH-133 had similar effects on weight bearing in this model. Pre-administered HU210 also significantly decreased carrageenan-induced changes in paw volume (P < 0.001), this was not the case for JWH-133. Effects of post-administered HU210 and JWH-133 on ipsilateral hindpaw weight bearing and paw volume were comparable to the effect of systemic post-administration of morphine and rofecoxib (3 mg/kg for both). In summary, both HU210 and JWH-133 attenuated established inflammatory hypersensitivity and swelling, suggesting that cannabinoid-based drugs have clinical potential for the treatment of established inflammatory pain responses.     

The cyclooxygenase-2 inhibitor GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine] is effective in animal models of neuropathic pain and central sensitization

The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for rofecoxib and 6.6 mg/kg p.o. for celecoxib. However, in contrast to celecoxib (5 mg/kg p.o. b.i.d.) and rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect, GW406381X (5 mg/kg p.o. b.i.d.) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitization, when given intrathecally (ED(50) = 0.07 mug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including central nervous system penetration, enzyme kinetics, and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitization, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared with celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.     

Non-steroidal anti-inflammatory drugs and tramadol in the treatment of osteoarthrosis deformans in patients with arterial hypertension

The prohypertensive effect of non-steroidal anti-inflammatory drugs (NSAIDs) can be manifested by the decreased efficiency of antihypertensive therapy. The tactics of their differential use in relation to the its effect on blood pressure (BP) in patients with osteoarthrosis (OA) and arterial hypertension (AH) has not been developed for the most effective and safe therapy. In this connection, it is extremely urgent to study the comparative safety of used NSAIDs as to their prohypertensive effect and to work out the management of patients with AH and OA. Ninety-eight patients with second-third degree OA of the knee and hip joints concurrent with the pain syndrome and first-second grade AH were followed up. Diclofenac, ketoprofen, arthrotec, nimesulide, and meloxicam were used. In a control group, the analgesic tramadol was supplemented to the therapy. AH was controlled by enalapril monotherapy. In groups of patients receiving diclofenac, arthrotec, meloxicam, and ketoprofen, there was a trend for the number of cases of an adequate nocturnal BP lowering (Dipper) to reduce and for those of an inadequate nocturnal BP decrease (Non-dipper), which may be accounted for by the prohypertensive effect of these drugs; this trend was most pronounced in the diclofenac and arthrotec groups. Despite its marked prohypertensive effect, nimesulide did not impair circadian BP variations. The central-acting analgesic tramadol exerted no prohypertensive effect and it did not increase BP values. The prohypertensive effect of the tested NSAIDs and tramadol increases in the following order: tramadol, ketoprofen, meloxicam, nimesulide, arthrotec, diclofenac.     

Interactions between aspirin and COX-2 inhibitors or NSAIDs in a rat thrombosis model

Recent in vitro studies, clinical trials and epidemiological studies have suggested possible interactions between aspirin and other cyclo-oxygenase (COX) inhibitors, such as ibuprofen of the COX-2 inhibitors celecoxib and rofecoxib. The objective of this study was to test the effects of aspirin (1, 2.5 and 5 mg/kg), and ibuprofen (4 and 15 mg/kg), diclofenac (2.5 mg/kg), flurbiprofen (2 mg/kg), celecoxib (7.5 mg/kg), and rofecoxib (1 mg/kg), alone or combined on a rat model of arterial thrombosis. Drugs were given orally daily for 7 days, before insertion of an arterio-venous shunt thrombosis system, left in place for 15 min. Main parameter was thrombus weight. Five to 12 rats were used per experiment, and 35 controls overall. Aspirin inhibited thrombus formation in a dose-dependent manner. All NSAIDS given alone also inhibited thrombus formation to approximately the same level as aspirin 1 mg/kg/day. Ibuprofen, celecoxib and rofecoxib inhibited the effects of aspirin, but not diclofenac or flurbiprofen. The interactions with aspirin do not seem to affect all NSAIDs to equal levels. The clinical impact of this needs to be confirmed in adequately powered clinical trials or pharmaco-epidemiological studies.     

A comparison of rofecoxib versus celecoxib in treating pain after dental surgery: a single-center,randomized, double-blind,placebo- and active-comparator-controlled,parallel-group,single-dose study using the dental impaction pain model

BACKGROUND: Rofecoxib and celecoxib, selective cyclooxygenase-2 inhibitors, have analgesic efficacy similar to that of nonselective nonsteroidal anti-inflammatory drugs. OBJECTIVE: This study was designed to confirm earlier findings that the overall analgesic efficacy of rofecoxib 50 mg was superior to that of celecoxib 200 mg and to extend the comparison to include celecoxib 400 mg. METHODS: In this single-center, randomized, double-blind, placebo- and active-comparator-controlled, parallel-group, single-dose study, patients who experienced moderate or severe pain after surgical extraction of at least 2 third molars received a single oral dose of either rofecoxib 50 mg, celecoxib 400 mg, celecoxib 200 mg, ibuprofen 400 mg, or placebo. Patients recorded scores of pain intensity, pain relief, and global assessment at prespecified time intervals throughout the 24-hour period after dosing. The end points were total pain relief (TOPAR) score over 8 hours (TOPAR8; primary end point), TOPAR score over 12 hours (TOPAR12), sum of pain intensity difference (SPID) over 8 and 12 hours (SPID8 and SPID12), patient's global assessment of study drug at 8 hours, time to confirmed perceptible pain relief (ie, time to onset of analgesic effect), peak pain intensity difference (PID), peak pain relief, time to first dose of rescue medication (ie, duration of analgesic effect), and percentage of patients using rescue medication. RESULTS: A total of 482 patients (358 females, 124 males; mean age, 22.1 years) were enrolled. Rofecoxib 50 mg (n = 151 patients) demonstrated significantly greater overall analgesic efficacy compared with celecoxib 400 mg (n = 151), as measured by TOPAR8 (least squares mean [SE] 17.2 [0.8] vs 15.0 [0.8]; P < 0.05) and TOPAR12 (25.3 [1.2] vs 21.0 [1.2]; P < 0.05), as well as a significantly longer duration of analgesic effect (P < 0.05). Time to onset of analgesic effect and peak analgesic effect were similar for rofecoxib 50 mg and celecoxib 400 mg. Rofecoxib also showed significantly greater overall analgesic efficacy than did celecoxib 200 mg (n = 90), including greater TOPAR8 scores (17.2 [0.8] vs 11.5 [1.1]; P < 0.001), faster onset of analgesic effect (P < 0.001), greater peak analgesic effect (P < 0.001 for peak pain relief and peak PID), and longer duration of analgesic effect (P < 0.001). The overall analgesic efficacy of rofecoxib 50 mg was similar to that of ibuprofen 400 mg (n = 45), except that the duration of analgesic effect of rofecoxib 50 mg was significantly longer (P < 0.001). All active treatments produced significantly greater overall analgesic efficacy compared with that of placebo (P < 0.001 for all scores [TOPAR8, TOPAR12, SPID8, SPID12, and patient's global assessment] for all study drugs). The adverse-events (AE) profile was generally similar in all treatment groups. The 3 most common AEs were nausea, postextraction alveolitis, and vomiting. CONCLUSIONS: In this study, rofecoxib 50 mg provided generally superior overall analgesic efficacy compared with that of celecoxib 400 and 200 mg, including a significantly longer duration of analgesic effect. The overall analgesic efficacy of rofecoxib 50 mg was generally similar to that of ibuprofen 400 mg, except for a significantly longer duration of analgesic effect.     

Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: a randomized,placebo-controlled clinical trial

BACKGROUND: Rofecoxib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. OBJECTIVE: The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. METHODS: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate to severe pain after the surgical extraction of > or = 2 third molars were randomized to receive a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPAR8) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2-stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. RESULTS: A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% experienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR24 was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with enteric-coated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and >4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (>24 hours vs 1 hour and 37 minutes). Enteric-coated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, although the rofecoxib group had a significantly lower incidence of clinical and drug-related adverse events than the enteric-coated diclofenac sodium group. CONCLUSIONS: A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours.     

Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase. The induction of COX-2 after inflammatory stimuli has led to the hypothesis that COX-2 inhibition primarily accounts for the therapeutic properties of NSAIDs. METHODS: Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX-isoform specific assays (serum thromboxane B2 [TXB2] and lipopolysaccharide [LPS]-stimulated whole blood prostaglandin E2 and assays of COX-1 and COX-2 activity, respectively). A double-blind, parallel-group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain. RESULTS: Rofecoxib showed a >800-fold COX-2 selectivity with use of CHO cells that express human COX-1 and COX-2. In subjects, dose- and concentration-dependent inhibition of LPS-stimulated prostaglandin E2 was observed with both rofecoxib (IC50 [the concentration estimated to produce 50% inhibition], 0.77 micromol/L) and indomethacin (IC50, 0.33 micromol/L). Whereas indomethacin inhibited TXB2, (IC50, 0.14 micromol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen (P > .20). All active treatments showed greater improvement than placebo (P < .001) CONCLUSIONS: Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2.     

A single-blind, randomized, controlled trial to assess the efficacy and tolerability of rofecoxib, diclofenac sodium, and meloxicam in patients with acute gouty arthritis

BACKGROUND: Acute attacks of gouty arthritis are characterized by the rapid onset of severe pain, swelling, and erythema of the affected joint. Nonsteroidal anti-inflammatory drugs are considered the drugs of first choice for treating acute gout. Rofecoxib is a specific cyclooxygenase-2 inhibitor, which has demonstrated analgesic efficacy in the setting of acute pain. Whether it is effective in the treatment of acute gouty arthritis remains to be evaluated. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of rofecoxib compared with diclofenac sodium sustained release (SR) and meloxicam in the treatment of acute gouty arthritis. METHODS: In this single-blind, randomized, controlled, parallel-group study, patients aged > or =18 years with acute gout within 48 hours of onset were randomized to receive oral treatment with 2 tablets of rofecoxib (25 mg), diclofenac (75 mg), or meloxicam (7.5 mg) once daily for 7 days. The primary outcome measures were patients global assessment of response to therapy and investigator assessment of response to therapy on days 3 and 8. Other efficacy measurements included investigator assessment of total inflammatory scores on days 3 and 8 and patient assessment of pain intensity during the first 12 hours of treatment. RESULTS: Sixty-two patients (53 men, 9 women; mean [SD] age, 51.1 [12.1] years) were assigned to receive rofexocib (n = 20), diclofenac (n = 21), or meloxicam (n = 21). For patient global response to therapy on days 3 and 8, rofecoxib was associated with analgesic efficacy in significantly more patients compared with meloxicam (84.2% vs 40.0% of patients [ P=0.005] and 94.7% vs 60.0% of patients [ P=0.02], respectively); no significant differences versus diclofenac were found. Similarly, for investigator global assessment of response to therapy, a greater percentage of responders was found in the rofecoxib group compared with the meloxicam group on day 3 (88.9% vs 40.0% of patients [ P=0.02 ]), but the difference was not significant on day 8. A greater percentage of responders was found in the rofecoxib group compared with the diclofenac group on day 3 (88.9% vs 47.3% [ P=0.007 ]), but the difference was not significant on day 8. Compared with baseline, all regimens showed significant improvement in total inflammatory scores on days 3 and 8 (all P<0.01 ). During the first 12 hours after dosing, pain intensity score was significantly reduced with rofecoxib starting at 0.5 hours ( P<0.05 ), but not with diclofenac or meloxicam. Clinical adverse events (AEs) were reported in 4 (20.0%), 7 (33.3%), and 6 (28.6%) patients in the rofecoxib, diclofenac, and meloxicam groups, respectively; the most common AEs reported were edema in 1 patient each in the rofecoxib (5.0%) and meloxicam (4.8%) groups and 2 patients (9.5%) in the diclofenac group and abdominal (1 [5.0%], 1 [4.8%], and 2 [9.5%], respectively). No significant differences in tolerability were found among the 3 treatment groups. CONCLUSIONS: In this study of patients with acute gouty arthritis, rofecoxib 50 mg once daily provided more effective treatment than diclofenac sodium SR 150 mg and meloxicam 15 mg administered orally once daily for 7 days in > or = 1 efficacy assessment of overall analgesic effect on day 3 or day 8. Rofecoxib achieved a rapid onset of pain relief, demonstrating significant improvement 30 minutes after dosing. All of the regimens appeared well tolerated in the population studied.     

Oral anti-hyperalgesic and anti-inflammatory activity of NK(1) receptor antagonists in models of inflammatory hyperalgesia of the guinea-pig

The oral analgesic and anti-inflammatory activity of NK(1) antagonists with species preference for the human receptor were assessed in (1) the carrageenan-induced inflammatory hyperalgesia and (2) Freund's complete adjuvant (FCA)-induced extravasation in the knee joint models of the guinea-pig, respectively. Mechanical hyperalgesia was determined by measuring the withdrawal threshold to a noxious mechanical stimulus applied to the paw and thermal hyperalgesia as the withdrawal latency to a noxious thermal stimulus applied to the plantar surface. A concentration of 1.0% carrageenan (intraplantar) reduced mechanical thresholds from 124+/-5 to 63+/-3 g and thermal latencies from 19+/-0.4 to 4.7+/-0.9 s as determined 4 h after injection. The hyperalgesia persisted for over 24 h. The NK(1) receptor antagonists, SDZ NKT 343, RPR100893 and SR140333, reduced mechanical hyperalgesia by 68, 36 and 27% at a dose of 30 mg kg(-1) p.o., respectively. No further reduction was noted at higher doses (maximum 100 mg kg(-1) p.o.). The anti-hyperalgesic effect of SDZ NKT 343 and RPR100893 peaked at 3 h while SR140333 produced maximal reversal at 1 h after oral administration. D(30) values indicated significant differences between the potency of these compounds. SDZ NKT 343 was by far the most potent anti-hyperalgesic agent (D(30): 1.1 mg kg(-1)). The D(30) values for RPR100893 and SR140333 were estimated to be 17 and >100 mg kg(-1), respectively. In thermal hyperalgesia, SDZ NKT 343 produced a significantly weaker anti-hyperalgesic effect with a peak of 25% reversal. The D(30) value for SDZ NKT 343 was 3.89 mg kg(-1). For comparison, morphine inhibited the carrageenan-induced mechanical and thermal hyperalgesia with an ED(50) of 1.85 and 2.51 mg kg(-1) s.c., respectively. When tested up to 300 mg kg(-1) p.o., aspirin reduced carrageenan-induced mechanical and thermal hyperalgesia by 55.0 and 45.2%, respectively. In addition to the anti-hyperalgesic effects of NK(1) receptor antagonists, the effects of SDZ NKT 343 and RPR100893 on plasma protein extravasation were measured in the FCA-treated knee joint of the guinea-pig. SDZ NKT 343 reversed plasma protein extravasation 2 h after administration by 60% at the oral dose of 30 mg kg(-1). RPR100893 was significantly less effective with a maximum reversal of 30% at 100 mg kg(-1). In comparison, indomethacin produced a 50% reversal at a 10 mg kg(-1) dose. These experiments indicate that the carrageenan-induced hyperalgesia in the guinea-pig may be predictive of analgesic activity of NK(1) receptor antagonists in man. NK(1) receptor antagonists are active anti-hyperalgesic drugs in both mechanical and thermal hyperalgesia in the guinea-pig. In addition they inhibit plasma protein extravasation in the same species. The variability of in vivo potency and efficacy of the NK(1) receptor antagonists in the mechanical hyperalgesia model is difficult to interpret as all compounds are highly effective at blocking the NK(1) receptor in guinea-pig tissues. Amongst several possibilities, differences in pharmacokinetics may explain discrepancies.     

Pemedolac: a novel and long-acting non-narcotic analgesic

Pemedolac [cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)-pyrano [3,4-b]indole-1-acetic acid; AY-30,715] exhibited potent analgesic effects against chemically induced pain in rats and mice and against inflammatory pain in rats. In each of the animal models used the analgesic potency of pemedolac was defined by an ED50 of 2.0 mg/kg p.o. or less. Significant analgesic activity was detected in rats at 16 hr after administration of 1 mg/kg p.o. (paw pressure test) and at 10 hr after administration of 10 mg/kg p.o. to mice (p-phenylbenzoquinone writhing). Inasmuch as pemedolac was inactive in the hot plate and tail-flick tests; and its analgesic activity was not antagonized by naloxone (1 mg/kg s.c.), and tolerance did not develop upon multiple administration; this drug does not exert its analgesic effects through an opiate mechanism. Pemedolac differed from standard nonsteroidal anti-inflammatory drugs (NSAIDs) in that the doses which produced analgesia were much lower than those required for either anti-inflammatory or gastric irritant effects. In acute anti-inflammatory tests, pemedolac exhibited only weak activity as evidenced by an ED50 approximately 100 mg/kg p.o. in the carrageenan paw edema procedure. This demonstrates for pemedolac a separation of at least 50-fold between the acute analgesic and anti-inflammatory activities, which was greater than that observed with reference NSAIDs. The compound also had a low ulcerogenic liability with an acute UD50 = 107 mg/kg p.o. and a subacute UD50 estimated to be 140 mg/kg/day p.o. In contrast, the reference NSAIDS (piroxicam, indomethacin, naproxen and ibuprofen) exhibited similar dose-response relationships for the analgesic, anti-inflammatory and gastric irritant effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of rofecoxib and oxycodone plus acetaminophen in the treatment of acute pain: a randomized, double-blind, placebo-controlled study in patients with moderate to severe postoperative pain in the third molar extraction model

BACKGROUND: Opiates, acetaminophen, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2-selective inhibitors such as rofecoxib are used in the treatment of acute pain because of their anti-inflammatory and/or analgesic properties. Rofecoxib has demonstrated an improved gastrointestinal safety profile compared with nonselective NSAIDs. OBJECTIVE: The aim of this study was to compare the analgesic efficacy and tolerability profile of rofecoxib 50 mg with those of the centrally acting, nonsalicylate, opiate/nonopiate analgesic combination oxycodone/acetominophen 5/325 in patients with pain after dental surgery. METHODS: In this randomized, double-blind, placebo- and active comparator-controlled study, patients experiencing moderate to severe postoperative pain after extraction of > or =2 third molars (including > or =1 mandibular impaction) received a single oral dose of rofecoxib 50 mg, oxycodone/acetaminophen 5/325 mg, or placebo. End points included total pain relief over 6 hours (TOPAR6, the primary end point) and 4 hours (TOPAR4), patient's global assessment of treatment at 6 hours (GLOBAL6) and 24 hours (GLOBAL24), summed pain intensity difference over 6 hours (SPID6), onset of analgesic effect (time to perceptible/meaningful pain relief, using a 2-stopwatch method), peak pain relief (PEAKPR), peak pain intensity difference (PEAKPID), and duration of analgesic effect (time to use of rescue analgesia). RESULTS: Two hundred twelve patients (63% female, 37% male; 76% white, 24% other; mean [SD] age, 20.9 [4.4] years; age range, 16-41 years) were enrolled in the study and received a single oral dose of rofecoxib 50 mg (n = 90), oxycodone/acetaminophen 5/325 mg (n = 91), or placebo (n = 31). The analgesic effect of rofecoxib was significantly greater than that of oxycodone/acetaminophen at P < 0.001 for TOPAR6, TOPAR4, GLOBAL6, GLOBAL24, and SPID6; at P < 0.010 for PEAKPR and PEAKPID; and at P < 0.001 for median time to use of rescue analgesia. Significantly fewer patients in the rofecoxib group (72.2%) took rescue analgesia within 24 hours postdose compared with the oxycodone/acetaminophen group (94.5%; P < 0.001) and the placebo group (96.8%; P < 0.02). Both active treatments were similar with respect to onset of analgesic effect. Both were generally well tolerated; the overall incidence of adverse experiences in the rofecoxib, oxycodone/acetaminophen, and placebo groups was 51.1%, 64.8%, and 48.4%, respectively. Rofecoxib was associated with a significantly lower incidence of nausea (18.9% vs 39.6%; P < 0.001) and vomiting (6.7% vs 23.1%; P < 0.001) compared with oxycodone/acetaminophen. CONCLUSIONS: In study patients with moderate to severe pain after dental surgery, rofecoxib 50 mg had a greater analgesic effect than oxycodone/acetaminophen 5/325 mg and was associated with less nausea and vomiting.     

Levetiracetam Interacts Synergistically With Nonsteroidal Analgesics and Caffeine to Produce Antihyperalgesia in Rats

Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10–200 mg/kg), ibuprofen (12.5–100 mg/kg), celecoxib (3.75–30 mg/kg), paracetamol (50–200 mg/kg), caffeine (15–100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1–50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED₅₀ in the presence of caffeine was reduced approximately 11-fold.