Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: A randomized, controlled trial

doi:10.1016/S0149-2918(99)80016-2

Clinical Therapeutics

Volume 21, Issue 6, June 1999, Pages 943-953

https://doi.org/10.1016/S0149-2918(99)80016-2 Get rights and content

Abstract

Previous data have suggested that rofecoxib, a cyclooxygenase (COX)-2-specific inhibitor, had analgesic effects similar to those of the nonsteroidal anti-inflammatory drugs when tested in the post-dental surgery pain model. The objective of this parallel-group, double-masked, randomized, placebo- and active comparator-controlled clinical trial was to assess more fully the analgesic efficacy of rofecoxib in the treatment of postoperative dental pain. After dental surgery, 151 patients (50.3% women; mean age, 18.3 years; 93.4% white) experiencing moderate-to-severe pain were to receive a single dose of placebo, rofecoxib 50 mg, or ibuprofen 400 mg. Analgesic efficacy was assessed for up to 24 hours postdose using self-administered questionnaires. Tolerability was assessed using spontaneous reports of adverse experiences, physical findings, and laboratory measurements. The results of this study demonstrated that rofecoxib 50 mg was more effective than placebo on all measures of analgesic efficacy. Rofecoxib 50 mg exhibited overall analgesic effects, onset of analgesia, and peak analgesic effects that were not significantly different from those of ibuprofen 400 mg, with a significantly longer duration of action (P < 0.05). We concluded that rofecoxib was efficacious in the treatment of postoperative dental pain and that COX-2-derived prostanoids play a role in treatment of the pain associated with dental surgery.

References (24)

RoszkowskiMT et al.
Effect of NSAID administration on tissue levels of immunoreactive prostaglandin E2, leukotriene B4, and (s) -flurbiprofen following extraction of impacted third molars
Pain
(1997)
SmithTJ
Cyclooxygenases as the principal targets for the action of NSAIDs
Rheum Dis Clin North Am
(1998)
DeWittD
Prostaglandin endoperoxide synthase: Regulation of enzyme expression
Biochim Biophys Acta
(1991)
YamagataK et al.
Expression of a mitogen-inducible cyclooxygenase in brain neurons: Regulation by synaptic activity and glucocorticoids
Neuron
(1993)
MeadeEA et al.
Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs
J Biol Chem
(1993)
KargmanS et al.
Mechanism of selective inhibition of human prostaglandin G/H synthase-1 and-2 in intact cells
Biochem Pharmacol
(1996)
BergJ et al.
Isoenzyme specific cyclooxygenase inhibitors: A whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line mono mac 6
J Pharmacol Toxicol Methods
(1997)
CooperSA
Five studies on ibuprofen for postsurgical dental pain
Am J Med
(1984)
ForbesJA
Oral surgery
SeibertK et al.
Role of inducible cyclooxygenase (COX-2) in inflammation
Receptor
(1994)

KömhoffM et al.

Localization of cyclooxygenase-1 and-2 in adult and fetal human kidney: Implication for renal function

Am J Physiol

(1997)

O'NeillGP et al.

Overexpression of human prostaglandin G/H synthase-1 and-2 by recombinant vaccinia virus: Inhibition by nonsteroidal anti-inflammatory drugs and biosynthesis of 15-hydroxyeicosatetraenoic acid

Mol Pharmacol

(1994)

Cited by (193)

Assay Sensitivity of Pain Intensity Versus Pain Relief in Acute Pain Clinical Trials: ACTTION Systematic Review and Meta-Analysis
2015, Journal of Pain
The magnitude of the effect size of an analgesic intervention can be influenced by several factors, including research design. A key design component is the choice of the primary endpoint. The purpose of this meta-analysis was to compare the assay sensitivity of 2 efficacy paradigms: pain intensity (calculated using summed pain intensity difference [SPID]) and pain relief (calculated using total pain relief [TOTPAR]). A systematic review of the literature was performed to identify acute pain studies that calculated both SPIDs and TOTPARs within the same study. Studies were included in this review if they were randomized, double-blind, placebo-controlled investigations involving medications for postsurgical acute pain and if enough data were provided to calculate TOTPAR and SPID standardized effect sizes. Based on a meta-analysis of 45 studies, the mean standardized effect size for TOTPAR (1.13) was .11 higher than that for SPID (1.02; P = .01). Mixed-effects meta-regression analyses found no significant associations between the TOTPAR – SPID difference in standardized effect size and trial design characteristics. Results from this review suggest that for acute pain studies, utilizing TOTPAR to assess pain relief may be more sensitive to treatment effects than utilizing SPID to assess pain intensity.
The results of this meta-analysis suggest that TOTPAR may be more sensitive to treatment effects than SPIDs are in analgesic trials examining acute pain. We found that standardized effect sizes were higher for TOTPAR compared to SPIDs.
Efficacy and Safety of Additional 200-mg Dose of Celecoxib in Adult Patients With Postoperative Pain Following Extraction of Impacted Third Mandibular Molar: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase II Study in Japan
2012, Clinical Therapeutics
Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought.
Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar.
This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests.
A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as “good” or “excellent” ≥2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%).
Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113.
A Double-Blind Randomized Controlled Trial of Rofecoxib and Multidose Oxycodone/Acetaminophen in Dental Impaction Pain
2007, Journal of Oral and Maxillofacial Surgery
Evaluation of the anti-inflammatory and analgesic activity of Me-UCH9, a dual cyclooxygenase-2/5-lipoxygenase inhibitor
2007, Life Sciences
Recently, we reported the dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) activity by some phenylsulphonyl urenyl chalcone derivatives. 2,4-dichloro-4′N[N′(4″methylphenylsulphonyl)urenyl] chalcone (Me-UCH9), was selected in the present study to determine its potential anti-inflammatory and analgesic effect after oral administration in several animal models related to the activation of COX-2 and 5-LO pathways. In the zymosan stimulated mouse air pouch model, Me-UCH9, reduced in a dose-dependent manner leukotriene B₄ (LTB₄) levels in pouch exudates obtained at 4 h, as well as prostaglandin E₂ (PGE₂) generated through COX-2 activation at 24 h. Tumor necrosis factor α (TNF-α) and myeloperoxidase activity were also strongly inhibited in this model. Me-UCH9 significantly reduced granulome size and vascular index determined in the murine air pouch granuloma model of angiogenesis. In the carrageenan-induced paw edema, this compound inhibited inflammatory response and pain, as well as PGE₂ and LTB₄ content in paw edematous fluid. Analgesic properties were corroborated in the murine phenyl-p-benzoquinone-induced writhing test. Finally, Me-UCH9 exerted anti-inflammatory effects in the chronic model of rat adjuvant-induced arthritis, both inhibiting paw swelling and reducing PGE₂ content. Our findings confirm that Me-UCH9 can modulate inflammatory and nociceptive responses in relation to the dual inhibition of COX-2 and 5-LO activities presented by this compound.
Analgesic efficacy of the cyclooxygenase-inhibiting nitric oxide donor AZD3582 in postoperative dental pain: Comparison with naproxen and rofecoxib in two randomized, double-blind, placebo-controlled studies
2006, Clinical Therapeutics
This study assessed the analgesic efficacy of single doses of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (AZD3582) in acute postoperative dental pain after the removal of an impacted mandibular third molar (ie, wisdom tooth).
Two randomized, placebo-controlled, double-blind studies were performed. In a dose-finding study, 242 patients were randomized to AZD3582 375, 750, 1500, or 2250 mg (n = 41, 37, 42, and 41, respectively); naproxen 500 mg (n = 39); or placebo (n = 42). In a comparator study, 282 patients were randomized to AZD3582 500 mg (n = 78) or 750 mg (n = 83), rofecoxib 50 mg (n = 80), or placebo (n = 41). Primary outcomes included time to rescue medication, time to pain relief, and mean pain intensity difference (MPID), as well as safety profile. Pain was rated on a visual analog scale.
In the dose-finding study, 52% (126/242) were women; the mean (SD) age was 25.1 (4) years, mean weight was 69.0 kg, and the mean (SD) body mass index (BMI) was 23.7 (3) kg/m². In the comparator study, 58% (164/282) were women; the mean (SD) age was 27 (6.4) years, mean weight was 71 kg, and mean (SD) BMI was 24.2 (3) kg/m². In the dose-finding study, the AZD3582 750-, 1500-, and 2250-mg groups were superior to placebo in the primary variables “time to rescue medication (0–8 hours)” (hazard ratios [HRs] [95% CIs], 0.17 [0.07–0.42], P < 0.003; 0.23 [0.11–0.50], P < 0.001; and 0.15 [0.06–0.36], P < 0.001, respectively), “time to meaningful pain relief” (HRs [95% CIs], 3.42 [1.87–6.25], P < 0.003; 2.49 [1.37–4.50], P < 0.003; and 3.07 [1.70–5.55], P < 0.001, respectively), and MPID (analysis of covariance [ANCOVA] least squares mean [LSM] differences [95% CIs], 25.8 [17.3–34.4], P < 0.003; 20.4 [12.1–28.7], P < 0.003; and 29.3 [20.9–37.6], P < 0.001, respectively). AZD3582 and naproxen did not show any statistically significant differences for the 3 primary variables, except that naproxen was superior to the AZD3582 375-mg dose for the variables time to meaningful pain relief (HR difference, 0.48 [95% CI, 0.29–0.78], P < 0.004) and MPID (difference in ANCOVA LSM, -10.2, [95% CI, -18.2 to -2.2], P < 0.012). The median times to meaningful pain relief were 115 minutes for AZD3582 375 mg, 66 minutes for 750 mg, 85 min utes for 1500 mg, 81 minutes for 2250 mg, and 162 minutes for placebo (P = NS, P = 0.003, P < 0.003, and P < 0.001, respectively). The median time tofirst res cue medication was 144 minutes for placebo, and <50% of the subjects on any of the AZD3582 doses or naproxen took rescue medication within 8 hours after dosing. In the comparator study, AZD3582 750 mg was superior to placebo in “time to rescue medicaton (0-24 hours)” (HR [95% CI], 0.4 [0.3-0.6], P < 0.001), “time to confirmed perceptible pain relief” (2.1 [1.1–3.8], P = 0.02), and MPID (11.9 [4.2–19.5], P = 0.002). However, inferiority of AZD3582 to rofecoxib for MPID could not be excluded (tolerance limit of 10 mm; P = NS for noninferiority testing). The median times to confirmed perceptible pain relief were 45 minutes for AZD3582 500 mg, 40 minutes for 750 mg, and 37 minutes for rofecoxib. The median times tofirst rescue medication were 218 minutes for AZD3582 500 mg, 365 minutes for 750 mg, 635 minutes for rofecoxib, and 90 minutes for placebo. Overall, AZD3582 was well tolerated. However, an effect on orthostatic blood pressure could not be excluded because there seemed to be more subjects with dizziness and orthostatic blood pressure reduction who were administered AZD3582 ≥750 mg. The proportions of patients with vertigo and decreased orthostatic blood pressure each group were as follows: AZD3582 500 mg, 6%; AZD3582 750 mg, 12%; rofecoxib, 3%; and placebo, 5%.
AZD3582 750 mg had similar analgesic efficacy as equimolar doses of naproxen, but noninferiority to rofecoxib was not demonstrated.
A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction
2011, Clinical Journal of Pain
To evaluate the postoperative analgesic efficacy of GW842166, a noncannabinoid CB2 agonist, in patients undergoing third molar tooth extraction.
This randomized, double-blind, placebo-controlled study compared the analgesic efficacy of single doses of GW842166 (100 or 800 mg) or ibuprofen with placebo in patients undergoing extraction of at least 1 fully or partially impacted third molar tooth. Eligible participants were dosed preoperatively within 1 hour of surgery. Participants allocated to active comparator received a second dose of ibuprofen (400 mg), 4 hours after the first 800 mg dose. Participants in the GW842166 and placebo groups received placebo at 4 hours. Procedures for the assessment of efficacy included a visual analog scale and verbal rating scale for scoring pain up to 10 hours postsurgery, duration of analgesia, patient global evaluation, proportion of patients requiring rescue medication, and elapsed time to rescue analgesia. Analysis of covariance was used to compare efficacy variables. Patient global evaluation was analyzed using Wilcoxon rank-sum tests and time to data was analyzed using the log-rank test.
Ibuprofen was significantly more effective than placebo across all endpoints. Trends for an improvement in pain scores for GW842166 800 mg failed to be of either clinical or statistical significance. GW842166 100 mg showed little separation from placebo. There was no evidence for any beneficial adjunctive effect after coadministration of rescue analgesia with GW842166. All treatments were well tolerated.
In comparison to ibuprofen, single doses of GW842166 (100 and 800 mg) failed to demonstrate clinically meaningful analgesia in the setting of acute dental pain.

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Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: A randomized, controlled trial

Abstract

Pain

Rheum Dis Clin North Am

Biochim Biophys Acta

Neuron

J Biol Chem

Biochem Pharmacol

J Pharmacol Toxicol Methods

Am J Med

Oral surgery

Role of inducible cyclooxygenase (COX-2) in inflammation

Receptor

Localization of cyclooxygenase-1 and-2 in adult and fetal human kidney: Implication for renal function

Am J Physiol

Overexpression of human prostaglandin G/H synthase-1 and-2 by recombinant vaccinia virus: Inhibition by nonsteroidal anti-inflammatory drugs and biosynthesis of 15-hydroxyeicosatetraenoic acid

Mol Pharmacol