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The Analgesic Effect of Etoricoxib Relative to That of Two Opioid- Acetaminophen Analgesics: a Randomized, Controlled Single-Dose Study in Acute Dental Impaction Pain*

Posted on: Thursday, 17 March 2005, 03:00 CST

Key words: Analgesia * Analgesics * Cyclo-oxygenase inhibitors * Etoricoxib * Opioids * Surgery, oral

ABSTRACT

Background: To compare the analgesic effect of single doses of etoricoxib 120 mg, oxycodone/ acetaminophen 10mg/650mg and codeine/ acetaminophen 60 mg/600 mg in acute pain using the dental impaction model.

Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6 h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioidrelated (nausea and vomiting) adverse experiences.

Results: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120 mg, oxycodone/acetaminophen 10 mg/650 mg, codeine/acetaminophen 60 mg/600 mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2 units) versus oxycodone/acetaminophen (10.2 units); and codeine/acetaminophen (6.0 units); ρ < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly (p<0.001) shorter for oxycodone/ acetaminophen (20 min) and numerically but not significantly shorter (P= 0.259) for codeine/acetaminophen (26 min) compared with etoricoxib (40 min). Etoricoxib (24 h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3 h), codeine/acetaminophen (2.7h), and placebo (1.7 h) (p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/ acetaminophen, specifically, significantly (p < 0.05) fewer episodes of nausea.

Conclusion: Etoricoxib 120 mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10 mg/650 mg and codeine/ acetaminophen 60 mg/600 mg.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the therapeutic agents of choice for the management of acute pain. NSAIDs are usually the first agents to be considered as they are efficacious in relieving acute pain in clinical settings such as dental surgery1. While NSAIDs can be used as the sole therapeutic agent for less severe pain, they cannot be used alone for more severe pain since a maximum effect is readily achieved (ceiling effect)2"4. Opioids provide significant dose-related pain relief, and are, therefore, readily implemented in acute pain settings5. The use of opioids, however, is often not well tolerated due to their dose-related side effects e.g., nausea and vomiting6. Furthermore, in some situations, NSAIDS may provide an analgesic effect that is at least as good as opioids, and as their tolerability profile is generally more favorable than opioids, they may be the preferred therapy.

COX-2 selective inhibitors have emerged as a new treatment choice in the management of acute pain7. These agents have the potential to provide efficacy that is similar to that of recommended doses of opioids, but without the opioid-related side effects that can hinder a patient's recovery from dental or surgical procedures. Etoricoxib is a new COX-2 selective inhibitor that has been shown to be effective in the management of acute pain associated with dental surgery, orthopedic surgery, acute gouty arthritis, and primary dysmenorrhea8-11.

In order to test the hypothesis that COX-2 selective inhibitors, such as etoricoxib, provide pain relief that is at least as effective as opioid therapeutic agents, a placebo-controlled dental surgery pain study was conducted in patients undergoing extraction of 2 or more third-molars, with at least one of the molars partially or completely embedded in mandibular bone. This study evaluated the analgesic effect and tolerability of etoricoxib 120mg in comparison to that of oxycodone/ acetaminophen 10mg/650mg as well as to that of codeine/acetaminophen 60 mg/600 mg. These opioidacetaminophen analgesics are commonly used for the treatment of acute postoperative dental pain12.

Patients and methods

This was a single-center study (Dental Center, PPD Development, Inc., Austin, Texas) conducted during the months of October and November 2001. The protocol and the consent form were approved by a central institutional review board (Research Consultants' Review Committee, Austin, Texas). All patients gave written informed consent before having any procedures performed.

Study design

This randomized, double-blind, placebo-controlled, parallel- group study assessed the analgesic effect of etoricoxib 120mg in comparison to oxycodone/ acetaminophen 10 mg/650 mg in a non- inferiority design. In addition, the analgesic effect of etoricoxib 120mg was compared with that of codeine/acetaminophen 60 mg/600 mg. Patients experiencing moderate or severe pain received tablets with active drug or matching placebo tablets, in a blinded fashion, according to a computer-generated allocation schedule in a ratio of 2:2:1:1 (etoricoxib 120mg; oxycodone/acetaminophen 10 mg/650 mg; codeine/acetaminophen 60 mg/600 mg; or placebo). Allocation was stratified by baseline pain intensity (moderate and severe pain). The study was comprised of 3 study visits: a screening visit, a surgery and treatment visit and a post-study visit. All patients reported pain intensity and pain relief over a 24-h period following the study drug administration and they remained in the clinic for the first 8 h. Rescue medication (acetaminophen/hydrocodone 500mg/ 5mg) was available for patients who did not receive sufficient pain relief from the study drug. All patients were informed that the study drug might not provide pain relief immediately; thus, they were advised not to take any additional analgesics during the first 90 min.

Patients

Eligible patients were healthy men and women, at least 16 years of age, who had 2 or more third molars to be removed, with at least one of the molars partially or completely embedded in mandibular bone. All patients had a physical examination, laboratory safety tests (hematology, blood chemistry and urinalysis) and a drug test performed at the screening visit. Abnormal physical examination, clinically significant laboratory abnormalities, or a positive drug screen excluded a patient from the study.

Women of childbearing potential had a negative pregnancy test and agreed to either remain abstinent or use appropriate contraception starting at the screening visit and through 7 days post-dose; pregnancy tests were performed at the screening visit, on the day of surgery, and at the post-study visit.

Before entering the study, patients stopped the use of all analgesic medications such as aspirin, acetaminophen, NSAIDs, opioids, or any other agents that could have confounded the analgesic and tolerability responses; the washout periods were between 6 h and 72 h, depending on the half-life of the respective drugs. Other medications that were specifically excluded were tricyclic antidepressants, antihistamines, tranquilizers, hypnotics, sedatives, or corticosteroids. Surgical anesthetics, such as nitrous oxide, xylocaine with epinephrine, diazepam, midazolam, methohexital, atropine, or fentanyl, were exempt from this exclusion.

Patient diary card

On a patient diary card, patients scored their pain intensity on a 0-3 scale (no pain to severe pain)13 and pain relief on a 0-4 scale (no pain relief to complete pain relief)13 at 16 pre- specified time points (15min, 30 min, 45min, 60min, 90min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 20 h, and 24 h) during the 24 h time period following the ingestion of study medication. At 6 h and 24 h post-dose, they scored the study drug on a 0-4 scale (poor to excellent). Patients also recorded when they took any rescue medication (acetaminophen/ hydrocodone) and the amount taken.

Efficacy endpoints

Pain relief and pain intensity scores were used to calculate the overall analgesic effect: total pain relief over the first 6 h (TOPAR6) and the sum of pain intensity difference over the first 6 h (SPID6). TOPAR6 was the primary endpoint, selected based on the shortest recommended dosing interval for oxycodone/ acetaminophen. In addition, TOPAR4 was evaluated since the shortest recommended dosing interval for codeine/acetaminophen is 4 h. Patient Global Evaluations (at 6 h and 24 h)provided patients' overall impression of the study medication.

Other endpoints assessed (1) the analgesic peak effect i.e., peak pain relief score (maximum pain relief score during the first 6 h post-dose; 0-4 scale) and peak pain intensity difference (PID) score (maximum difference from baseline pain intensity score during the first 6 h post-dose; -1 to 3 scale); (2) the time to onset of analgesia (median time to confirmed perceptible pain relief) using the 2-stopwatch method14 and percentage of patients experiencing onset of analgesia during the study (i.e. percentage of patients with a PID > 1); (3) the duration of analgesic effect (median time to the first dose of re\scue medication) and the percentage of patients requesting rescue medication. The number of tablets of rescue medication used during the 24-h study period was also a pre- specified endpoint.

Tolerability assessment

Spontaneously reported adverse experiences were collected; in a blinded fashion, the investigator determined whether or not the event could have been caused by study medication. A comparison of the number of episodes of nausea and vomiting in the etoricoxib and opioid groups was a pre-specified endpoint.

Statistical analyses

The efficacy analysis was a modified intention-to-treat analysis and included all randomized patients who had a moderate or severe baseline pain intensity score and at least one post-dose assessment. All randomized patients were included in tolerability assessments.

The primary hypothesis of the study was to determine if a single dose of etoricoxib 120mg was at least as effective in providing pain relief as a single dose of oxycodone/acetaminophen (10mg/650mg) over a 6-h time period. The pre-specified non-inferiority criteria were derived from previous etoricoxib dental pain studies11,15 and published data on oxycodone/ acetaminophen16,17. One hundred patients in each of the etoricoxib and oxycodone/acetaminophen groups would give 90% power to detect a significantly greater effect of etoricoxib 120 mg relative to oxycodone/acetaminophen 10mg/ 650mg, based on both statistical superiority and clinical superiority of at least 2.5 points on TOPAR6 (range 0-24). If the lower bound of the 95% confidence interval (CI) for the difference in TOPAR6 score was not lower than -2.5 units, then etoricoxib would be considered at least as effective as oxycodone/ acetaminophen. If this was achieved and the TOPAR6 difference exceeded 2.5 units and the lower bound was above O, etoricoxib would be considered superior to oxycodone/acetaminophen. The study also assessed the analgesic effect of etoricoxib 120mg in comparison to codeine/acetaminophen (60mg/600mg). Although no pre-specified non-inferiority criteria was defined for this comparison, the interpretation could be made using the criteria for the comparison to oxycodone/ acetaminophen.

TOPAR6 was analyzed by using a parametric analysisof-variance (ANOVA) model. The ANOVA model, Cox proportional hazards regression model, or logistic regression model was used in the analyses of the other endpoints, as appropriate. In each model, treatment and stratum (baseline pain intensity) were included as factors. The treatment-by-stratum interaction was tested and explored for impact on the results if it was significant at the α = 0.05 level.

Results

Patients

Of 404 screened patients, 302 patients were randomly allocated to one of the following treatments: etoricoxib 120mg (N = 100), oxycodone/ acetaminophen 10mg/650mg (N = 102), codeine/ acetaminophen 60mg/600mg (N = 50), and placebo (N = 50). The most common reasons for exclusion were: inability to understand the study procedures, not fulfilling the medical history requirement, and clinically significant laboratory abnormality at screening. Patient characteristics and baseline pain intensity were similar across the four treatment groups (Table 1). All patients completed the efficacy portion of the diary. However, one patient (oxycodone/ acetaminophen) did not return for the post-study visit. Thus, the amount of rescue medication and the episodes of nausea and vomiting were incompletely reported for this patient; the available data were included.

Etoricoxib versus oxycodone/ acetaminophen

Etoricoxib 120mg met and exceeded the predefined noninferiority criterion for the primary endpoint compared with oxycodone/ acetaminophen 10mg/650mg (Figure 1). The least squares (LS) mean TOPAR6 scores were 13.2units and 10.!units, respectively (Table 2). The overall analgesic effect assessed by SPID6 also showed that etoricoxib 120mg had a superior analgesic effect (Table 2). The patient global evaluation score at 6 h was similar for etoricoxib 120mg and oxycodone/ acetaminophen while at 24 h post-dose, etoricoxib was superior to oxycodone/acetaminophen (Table 2). At 6 h, the percentage of patients assessing the study drug as providing good, very good, or excellent responses were similar in the etoricoxib and oxycodone/acetaminophen groups (Figure 2). The peak analgesic effect for etoricoxib, as assessed by peak PID and peak pain relief, was also similar to that of oxycodone/acetaminophen. The percentage of patients experiencing onset of analgesia during the study was 77% in the etoricoxib group compared with 88% in the oxycodone/acetaminophen group and the time to onset of analgesia was 20 min for oxycodone/acetaminophen and 40 min for etoricoxib (p < 0.001 favoring oxycodone/acetaminophen] (Table 2). Forty-nine percent of patients on etoricoxib took rescue medication (additional analgesic medication) while 83% of the patients on oxycodone/ acetaminophen required additional analgesic medication to attain sufficient pain relief during the 24-h time period; the difference was statistically significant (p < 0.001). Specifically, during the first 6 h post-dose, 25% of etoricoxib patients took rescue medication versus 57% of oxycodone/ acetaminophen patients. This resulted in etoricoxib patients requiring significantly fewer tablets of rescue medication for breakthrough pain during the 24-h time period than those receiving oxycodone/acetaminophen; 1.3 tablets for the etoricoxib group compared with 2.5 tablets for the oxycodone/acetaminophen group(p < 0.001). The duration of the analgesic effect of etoricoxib lasted significantly longer (> 24 h) than that of oxycodone/acetaminophen (5.3h) (p < 0.001).

Table 1. Baseline patient characteristics

Etoricoxib versus codeine/acetaminophen

Etoricoxib 120mg demonstrated significant superior analgesic effect to codeine/acetaminophen for most of the endpoints (p < 0.001). The LS mean TOPAR6 scores were 13.2units and 6.0units for etoricoxib and codeine/acetaminophen, respectively (Figure 1 and Table 2). Etoricoxib showed greater effects for the SPID6 score and the patient global evaluation at 6 h, consistent with results for the primary endpoint (Table 2). Additionally, the LS mean TOPAR4 scores were 8.4 vs. 4.6 (p < 0.001) for etoricoxib and codeine/ acetaminophen, respectively (Table 2). At 6 h post-dose, fewer patients on codeine/acetaminophen reported good, very good, and excellent responses (46%) compared with those who received etoricoxib (72%) (Figure 3). Etoricoxib had significantly (p < 0.05) greater peak analgesic effect than codeine/acetaminophen, as assessed by peak PID and peak pain relief (Table 2). In regards to onset of analgesia, a similar percentage of patients in the codeine/ acetaminophen group (76%) experienced onset to that of the etoricoxib group (77%). However, codeine/ acetaminophen had a numerically but not significantly shorter median time to onset of analgesia compared with etoricoxib, 26min and 40min, respectively (p = 0.259) (Table 2). In the etoricoxib group, 49% of the patients used rescue medication during the first 24 h compared with 98% of the patients in the codeine/ acetaminophen group. During the first 6 h post-dose, 25% of etoricoxib patients took rescue medication versus 88% of codeine/acetaminophen patients. The LS mean number of rescue medication tablets taken for breakthrough pain during the 24- h time period by etoricoxib patients was significantly fewer than that taken by codeine/acetaminophen patients; 1.3 tablets for the etoricoxib group compared with 3.3 tablets for the codeine/ acetaminophen group (p < 0.001).

Figure 1. Efficacy comparability data: Etoricoxib 120mg versus oxycodone/acetaminophen 10mg/650mg and versus codeine/acetaminophen 60 mg/600 mg. Least-squares mean difference of total pain relief scores (TOPAR6) with 95 % confidence intervals are shown

Table 2. Summary of efficacy endpoints - LS mean (95% confidence interval)

Figure 2. Pain relief score over time. Patients scored their pain relief on a 0-4 scale (none, some, a little, a lot, and complete) at 16 timepoints post-dose. The least-squares mean with standard error (SE) are shown: placebo (open circles); etoricoxib 120mg (upright solid triangles); oxycodone/acetaminophen 10mg/650mg (closed circles); codeine/ acetaminophen 60 mg/600 mg (open squares)

Etoricoxib, oxycodone/acetaminophen, and codeine/acetaminophen versus placebo

All active treatment groups had significantly better analgesic effect compared with placebo (p < 0.001) for TOPAR6 (the primary endpoint), TOPAR4, SPID6, patient global evaluation, peak effect, as well as shorter time to onset (Figure 2 and Table 2). In addition, etoricoxib and oxycodone/acetaminophen had significantly longer duration compared with placebo, while the analgesic effect of codeine/acetaminophen (2.7h) was numerically but not significantly longer than that of placebo (1.7h) (Table 2). Patients receiving etoricoxib used significantly fewer tablets of rescue medication than placebo (1.3 vs. 3.0 tablets, respectively], while patients receiving oxycodone/acetaminophen (2.5 tablets) and codeine/ acetaminophen (3.3 tablets) required a similar number of tablets as those on placebo over the 24-h time period.

Tolerability

The percentage of patients taking etoricoxib who reported clinical adverse experiences was similar to that of patients taking placebo and generally lower than that of patients on either opioid treatment (Table 3). The most common adverse experiences were nausea, vomiting, post-extraction alveolitis, and dizziness. There were fewer episodes of nausea during the pre-specified 24-h post- dose period in the etoricoxib group (7.0%) than in the placebo group (16%); this may have been due to the greater use of opioid rescue medication or to a lack of pain relief in the placebo group. Furthermore, the etoricoxib patients experienced significantly fewer episodes of nausea during the 24-h post-dose timeperiod compared with oxycodone/acetaminophen (p < 0.001) and codeine/acetaminophen (p = 0.014) as well as significantly fewer episodes of vomiting compared with the oxycodone/acetaminophen group (p < 0.001). The incidence of vomiting was numerically lower for etoricoxib (4.0%) compared with codeine/acetaminophen (8.0%); this difference was not statistically significant. Dizziness occurred at a higher incidence in the oxycodone/acetaminophen group than in all other treatment groups and postextraction alveolitis occurred with similar incidences across all treatment groups, including placebo (Table 3). No serious adverse experiences were reported.

Figure 3. Patient global evaluation at 6 h post-dose. Patients rated the study medication they received to treat their pain using a scale of poor, fair, good, very good, and excellent. Percentage of patients reporting poor and fair versus good, very good, and excellent responses are shown

Discussion

This study demonstrated that etoricoxib (120mg), a COX-2 selective inhibitor, has superior overall analgesic efficacy to both oxycodone/acetaminophen (10mg/650mg) and codeine/acetaminophen (60 mg/600 mg) using the dental impaction model as assessed by the primary endpoint. This difference was primarily due to the prolonged duration of effect for etoricoxib. The tolerability profile of etoricoxib was similar to that of placebo with the overall incidences of adverse experiences lower than each of the opioid treatments, including significantly fewer episodes of nausea. These results are consistent with results from earlier reports in which etoricoxib 120 mg showed an analgesic effect superior to oxycodone/ acetaminophen 10 mg/650 mg with an improved tolerability profile18 and an analgesic effect superior to codeine/acetaminophen 60 mg/600 mg11.

A single dose of etoricoxib provided pain relief over 24 h, consistent with a once-daily dosing regimen, that resulted in significantly less rescue medication use compared with the two opioid analgesics. Single administrations of oxycodone/ acetaminophen and codeine/ acetaminophen provided pain relief over 5.3 h and 2.7 h, respectively, durations that are consistent with the respective recommended dosing regimens (dosing every 6 h or 4 h, respectively). Although the median time to onset of analgesia was more rapid with the opioid comparators versus etoricoxib, etoricoxib 120 mg provided an analgesic effect that was superior to that of both opioid analgesics over the first 4 h and 6 h as assessed by the endpoints, TOPAR4 and TOPAR6. Etoricoxib had a median time to onset of 40 min, which was significantly longer than that of oxycodone/ acetaminophen (20 min) and numerically, but not significantly longer than that of codeine/acetaminophen (26min). In other studies, etoricoxib 120 mg has exhibited rapid onset of analgesia; in one study the median time to onset as early as 24 min15, and in two other studies the onset occurred as early as 30 min, which was similar to codeine/ acetaminophen11,18. Together, these studies indicate that etoricoxib has a rapid onset of analgesia that ranges from 24 min to 40 min, a time to onset that is generally similar to that of codeine/acetaminophen and less rapid than that of oxycodone/ acetaminophen.

The adverse experience profile was notably different between etoricoxib and the opioid comparators, specifically for nausea and vomiting, which are two of the most common side effects with opioid use. In comparison to patients receiving oxycodone/acetaminophen, a significantly smaller percentage of patients receiving etoricoxib experienced nausea and vomiting and, in comparison to codeine/ acetaminophen, a significantly smaller percentage of patients receiving etoricoxib experienced nausea. The higher incidences of nausea and vomiting during the first 24 h with the opioid comparators appears to be primarily due to the use of oxycodone/ acetaminophen or, to a smaller extent, codeine/acetaminophen rather than the greater use of rescue medication since incidences of nausea were also generally higher in the opioid groups than in the placebo group.

Table 3. Tolerability data - clinical adverse experiences in ≥ 4.0% of patients

Etoricoxib and other COX-2 selective inhibitors have demonstrated efficacy in previous studies with patients experiencing acute pain from surgical procedures7'19. These studies also demonstrated a decrease in the amount of opioid rescue medication among patients taking COX-2 selective inhibitors; reduction of opioid usage has lead to these patients returning to normal activities at a faster rate compared with patients using greater amounts of opioids19.

Conclusion

In summary, etoricoxib 120 mg provided an overall analgesic effect that was superior to that of oxycodone/acetaminophen 10 mg/ 650 mg and codeine/ acetaminophen 60 mg/600 mg over 24 h as shown by statistically superior TOPAR4, TOPAR6, SPID, and Global scores versus both active comparators. Etoricoxib specifically provided an analgesic effect that was sustained over the entire 24-h time period. Etoricoxib also provided superior analgesic efficacy over the first 6- and 4-h time periods, consistent with recommended dosing intervals for oxycodone/ acetaminophen and codeine/ acetaminophen, respectively. Additionally, etoricoxib was generally safe and well tolerated and had a superior tolerability profile versus both opioid-containing analgesics, particularly with respect to nausea. These data from dental impaction surgery suggest that etoricoxib, as a sole therapeutic agent, is a valuable option for the treatment of acute pain.

Acknowledgment

This study was funded by a grant from Merck & Co., Inc.

The authors wish to thank Michelle Aversano for assistance with study start-up and monitoring; Becky Cook for site monitoring; Bernie Kotyuk for coordination of data management, George Grant DDS, PhD (dental surgeon), Janie Johnston (site manager); Anish Mehta (medical writer) for assistance with the manuscript; and Dr. Jan Markind for her critical review of the manuscript.

* This work was previously presented at the 2nd Joint Scientific Meeting of the American Pain Society and the Canadian Pain Society, Vancouver, BC, Canada, May 6-9, 2004

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2767_4, Accepted for publication: 15 November 2004

Published Online: 10 January 2005

doi:10.1185/030079904X17983

Kerstin Malmstrom a, Jennifer Ang a, James R. Fricke b, Sumiko Shingo a and Alise Reicin a

a Departments of Clinical Immunology and Analgesia, and Biostatistics, Merck Research Laboratories, Rahway, NJ, USA

b PPD Development, Dental Unit, Austin, TX\, USA

Address for correspondence: Dr Alise Reicin, Merck & Co., Inc, 126 East Lincoln Ave, RY34B-264, Rahway, NJ 07065, USA. Tel: +1 732 594 4519; Fax: +1 732 594 3120; email: alise reicin@merck.com

Copyright Librapharm Jan 2005

Source: Current Medical Research and Opinion

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