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PAIN MEDICINE

The Analgesic Efficacy of Etoricoxib Compared with Oxycodone/Acetaminophen in an Acute Postoperative Pain Model: A Randomized, Double-Blind Clinical Trial

David J. Chang, MD^*, Paul J. Desjardins, DMD PhD, Thomas R. King^*, Tara Erb, MS^*, and Gregory P. Geba, MD MPH^*

*Merck & Co., Inc., West Point, Pennsylvania; and Scirex Corporation, Austin, Texas

Address correspondence and reprint requests to Paul J. Desjardins, DMD, PhD, 3200 Red River, Ste. 300, Austin, TX 78705. Address e-mail to pdesjardins{at}scirex.com

	Abstract

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Our objective in this study was to compare the analgesic effects of etoricoxib and oxycodone/acetaminophen in a postoperative dental pain model. Patients experiencing moderate to severe pain after extraction of two or more third molars were randomized to single doses of etoricoxib 120 mg (n = 100), oxycodone/acetaminophen 10/650 mg (n = 100), or placebo (n = 25). The primary end-point was total pain relief over 6 h. Other end-points included patient global assessment of response to therapy; onset, peak, and duration of effect; and rescue opioid analgesic use. Active treatments were statistically significantly superior to placebo for all efficacy measures. Total pain relief over 6 h for etoricoxib was significantly more than for oxycodone/acetaminophen (P < 0.001). Patient global assessment of response to therapy at 6 and 24 h was superior for etoricoxib. Both drugs achieved rapid onset, although the time was faster for oxycodone/acetaminophen by 5 min. The peak effect was similar for both drugs. Compared with oxycodone/acetaminophen patients, etoricoxib patients experienced a longer analgesic duration, had a smaller percentage requiring rescue opioids during 6 and 24 h, and required less rescue analgesia during 6 and 24 h. Oxycodone/acetaminophen treatment resulted in more frequent adverse events (AEs), drug-related AEs, nausea, and vomiting compared with etoricoxib treatment. In conclusion, etoricoxib 120 mg provided superior overall efficacy compared with oxycodone/acetaminophen 10/650 mg and was associated with significantly fewer AEs.

IMPLICATIONS: In this study we used the dental pain model to compare the efficacy of etoricoxib and oxycodone/acetaminophen in the treatment of acute pain. As demonstrated by this study, etoricoxib offers rapid, effective, and durable analgesia with fewer incidences of nausea and vomiting while perhaps reducing the risk of postsurgical bleeding.

	Introduction

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The efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) for the treatment of pain and inflammation is due to inhibition of the cyclooxygenase (COX)-2 enzyme, whereas inhibition of the COX-1 enzyme may to lead to gastrointestinal toxicity and loss of normal platelet function (1). Etoricoxib is a selective inhibitor of the COX-2 enzyme (2) and is an effective analgesic, with a reduced risk of bleeding due to platelet dysfunction, gastrointestinal bleeds, and ulcers (3). Consistent with sparing of COX-1 inhibition, studies in healthy humans have demonstrated that etoricoxib does not inhibit platelet aggregation (4) or prolong bleeding time (4). Among 62 healthy volunteers, patients treated with etoricoxib 120 mg demonstrated reduced fecal blood loss and fewer endoscopically detectable lesions compared with patients treated with ibuprofen 800 mg over 4 wk (5). The half-life of etoricoxib in healthy humans is 22 h, consistent with once-daily dosing (6). Clinical studies have shown that etoricoxib is as effective as indomethacin in the treatment of acute gouty arthritis (7), and is also effective in the treatment of rheumatoid arthritis (8,9) and osteoarthritis (10,11).

The postoperative dental pain model is well validated and accepted for assessing the efficacy of analgesic medications (12). This model is standardized and sensitive and provides a reliable method for comparing analgesics in the treatment of acute pain. Opioid combination products, including oxycodone/acetaminophen, are effective analgesics (13) used in treating acute postoperative pain, such as pain experienced after dental impaction surgery (13–15). Despite their effectiveness, opioids are limited by side effects such as nausea, vomiting, somnolence, and dizziness (13,16).

The primary objective of this study was to compare the analgesic efficacy of etoricoxib 120 mg with oxycodone/acetaminophen 10/650 mg in the treatment of patients with acute postoperative dental pain. Oxycodone/acetaminophen 10/650 mg is a potent orally dosed opioid analgesic used for relief of moderate to moderately severe pain (16). Analgesic efficacy was assessed by overall analgesic effect; time to onset, peak, and duration of analgesic effect; and rescue opioid medication use. This study also examined the safety and tolerability of the drugs in the acute pain model.

	Methods

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Patients were eligible for enrollment if they were 16 yr of age and scheduled to undergo surgical extraction of two or more third molars, at least one of which was partially imbedded in mandibular bone. Patients were required to provide written informed consent before undergoing any study procedure. The study protocol and informed consent were approved by an independent IRB.

Exclusion criteria were allergic reactions or intolerance to aspirin, any NSAID, rofecoxib, oxycodone, acetaminophen, or hydrocodone bitartrate; concomitant use of tricyclic antidepressants, opioid analgesics, antihistamines, tranquilizers, hypnotics, sedatives, or systemic corticosteroids; history of asthma in association with nasal polyps; illicit drug use; alcohol abuse; and history of any illness or laboratory evaluations that might confound study results or pose additional risk to patients.

Intraoperative anesthetics allowed included lidocaine, diazepam, methohexital sodium, midazolam hydrochloride, atropine, nitrous oxide, and fentanyl. Four oral surgeons from one site performed the procedures.

This randomized, double-blind, placebo- and active comparator-controlled, single-dose, single-center study compared etoricoxib 120 mg, oxycodone/acetaminophen 10/650 mg, and placebo. The dose selection of etoricoxib was based on a previous dental pain dose-ranging study that evaluated several doses of etoricoxib (17). In that study, etoricoxib 120 mg in a single dose was the smallest dose that provided maximal efficacy in the treatment of dental pain; the analgesic efficacy was similar to that of ibuprofen 400 mg. Oxycodone/acetaminophen 10/650 mg is the maximum initial recommended dose for acute pain (16).

This study consisted of a prestudy visit, a treatment visit (surgery and randomization), and a poststudy visit 7–10 days after surgery. Patients were assigned for surgery to one of four oral surgeons at the study site. After undergoing third-molar extraction surgery, eligible patients who experienced moderate to severe pain were randomized to treatment with etoricoxib 120-mg tablets, oxycodone/acetaminophen 10/650-mg tablets, or placebo in a 4:4:1 ratio. Randomization was performed with a computer-generated allocation schedule and stratified on the basis of the patient’s pain intensity (moderate or severe) at baseline. Study medication tablets were administered as a single oral dose in a double-blind fashion by using exact matching placebo. The study medication was provided in labeled bottles. Each label contained the patient allocation number, the package identification number, the bottle type (A for etoricoxib or B for oxycodone/acetaminophen), and the number of tablets. Separate sealed envelopes were provided to the investigator to be opened in the event of a serious adverse event (AE). The coversheet of the drug identification contained the package identification number and the allocation number. The middle sheet contained the same information as the cover sheet and the drug identification. The back sheet was shaded. At the end of the study, all envelopes were returned to the sponsor. None of the study medications was encapsulated. Rescue opioid analgesic medication (hydrocodone bitartrate/acetaminophen 5/500 mg) was available at any time to all patients who did not experience satisfactory pain relief after receiving study medication. To allow for study medication to take effect, patients were encouraged not to use rescue medication during the first 90 min after dosing.

The primary efficacy end-point used to assess overall analgesic effect in this study was total pain relief over 6 h (TOPAR6). TOPAR6 was selected to be consistent with the shortest dosing interval for oxycodone/acetaminophen. Other end-points of overall analgesic efficacy included the sum of pain intensity differences 6 h (SPID6) and patient global assessment of response to therapy (PGART) at 6 and 24 h. Other efficacy end-points included time to confirmed perceptible pain relief with two stopwatches (onset of analgesic effect), peak pain relief during the first 6 h after dosing (peak analgesic effect), time to first rescue analgesic medication (duration of analgesic effect), and percentage of patients taking rescue opioid medication and the number of rescue medication tablets consumed (rescue medication use). We also evaluated the incidence of adverse events (AEs), including the prespecified incidence of nausea and vomiting.

Patients recorded pain symptoms at 15, 30, 45, 60, and 90 min and 2, 3, 4, 5, 6, 12, and 24 h after the administration of study medication. Pain relief was recorded on a five-point scale (0 = none, 1 = a little, 2 = some, 3 = a lot, 4 = complete). The pain intensity was recorded on a four-point scale (0 = none, 1 = slight, 2 = moderate, 3 = severe). TOPAR6 was calculated by multiplying the pain relief score at each time point by the duration (in hours) since the preceding time point and summing these values up to 6 h. PID scores were calculated as the difference between baseline pain intensity and the pain intensity at each subsequent time point. SPID6 was calculated by multiplying the PID score at each postdose time point by the duration (in hours) since the preceding time point and summing these values up to 6 h. PGART was assessed by patients at 6 and 24 h after the administration of study medication on a five-point scale (0 = poor, 1 = fair, 2 = good, 3 = very good, 4 = excellent). Two stopwatches were started at the time of administration of study medication. When perceptible pain relief was achieved, the patient stopped the first stopwatch; when meaningful pain relief was achieved, the patient stopped the second stopwatch. Confirmed perceptible pain relief was defined as the time to perceptible pain relief (the first stopwatch time) for those patients who experienced meaningful pain relief (the second stopwatch time) (18). If perceptible pain relief was achieved without associated meaningful pain relief, a censored value of 4 h was used in the survival analysis of the stopwatch times.

Patients were required to remain at the study site for 6 h after dosing of the study medication. Self-assessments of efficacy at 12 and 24 h were performed with take-home diaries after the patients had been discharged from the study site. Patients who took any rescue analgesic medication recorded the date, time, and amount of medication taken. Immediately before taking the first dose of rescue medication, patients recorded assessments of pain intensity, pain relief, and global assessment. No further efficacy measurements were recorded after the first dose of rescue medication was taken.

The safety profile of the study medications was determined by recording observed or reported AEs. For each AE, the investigator rated the intensity, action taken, and relationship of the AE to the study drug as definitely not related, probably not related, possibly related, probably related, and definitely related. AEs that were determined by investigators to be possibly, probably, or definitely related were considered to be drug related. The incidences of nausea and vomiting were of special interest and were predefined in the data-analysis plan.

Efficacy analyses were based on a modified intention-to-treat approach; all patients with a baseline assessment of moderate to severe pain intensity and at least one pain assessment after dosing were included in the analyses. The primary objective of this study was to determine TOPAR6 of a single oral dose of etoricoxib 120 mg compared with a single oral dose of oxycodone/acetaminophen 10/650 mg. On the basis of dental pain studies comparing etoricoxib 120 mg and placebo (17,19) and dental pain studies comparing oxycodone/acetaminophen with placebo (14,15), a sample size of 100 patients per active treatment group was calculated to provide 90% power to declare that etoricoxib 120 mg was superior to oxycodone 10 mg/acetaminophen 650 mg, on the basis of both statistical superiority and clinical superiority of at least 2.5 points on TOPAR6 (range, 0 to 24). Pairwise treatment comparisons of least-square means for TOPAR6, SPID6, PGART, peak pain relief, and mean number of rescue medication tablets taken were analyzed with an analysis of variance model with factors for treatment group and baseline pain intensity. A logistic regression model with factors for treatment and baseline pain intensity was used in the analysis of the percentage of patients taking rescue medication and PGART responders (the percentage of patients with responses of "good," "very good," or "excellent"). The prespecified analysis to compare PGART responders among the treatment groups was to use odds ratios (ORs) from this logistic regression model. For the purpose of this analysis, ORs were calculated as the number of times a PGART response occurred divided by the number of times a PGART response did not occur, divided by the odds for the same event in another comparator group. Analyses of time to confirmed perceptible pain relief and time to rescue medication were performed with Kaplan-Meier time-to-event curves along with the corresponding Wilcoxon’s statistics.

All randomized and treated patients (all patients who consumed study medication) were included in the safety assessments. Fisher’s exact test was used to compare treatment groups with respect to the percentage of patients who experienced one or more AEs, drug-related AEs, and specific AEs, such as nausea or vomiting.

	Results

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A total of 225 patients were randomized to treatment with etoricoxib 120 mg (n = 100), oxycodone/acetaminophen 10/650 mg (n = 100), or placebo (n = 25). The baseline demographic characteristics were similar among groups. Overall, 60% of patients were female (135 of 225), and 64% were Caucasian (144 of 225). Approximately 51% of patients (114 of 225) reported moderate pain after surgery, and 49% (111 of 225) reported severe pain (Table 1). The use of intraoperative anesthesia was limited to epinephrine administered with lidocaine hydrochloride, nitrous oxide, fentanyl, and diazepam and is detailed in Table 1.

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean ± SE pain relief scores in patients experiencing moderate to severe postoperative dental pain over the 6 h after dosing.

View larger version (16K): [in this window] [in a new window]   Figure 2. Primary efficacy end-point: total pain relief (TOPAR) scores over 6 h. aP < 0.001 versus placebo; bP < 0.001 versus oxycodone/acetaminophen.

Mean PGART scores at 6 and 24 h are shown in Table 2. Patients treated with etoricoxib reported a higher global response than patients treated with oxycodone/acetaminophen (P < 0.05) at 6 and 24 h (P < 0.01). Both etoricoxib and oxycodone/acetaminophen scores were greater than placebo scores at both 6 and 24 h (P < 0.001 for all comparisons). On the basis of PGART scores at 6 h, the percentage of patients who were "responders" (with a good to excellent rating) for etoricoxib, oxycodone/acetaminophen, and placebo was 78.6%, 72.2%, and 12.5%, respectively. The OR for responders comparing etoricoxib with oxycodone/acetaminophen was 1.42, favoring the former (P = 0.301). The percentage of responders was also larger for etoricoxib compared with placebo (OR, 26.30; P < 0.001) and was larger for oxycodone/acetaminophen compared with placebo (OR, 18.58; P < 0.001) (Table 3). Similar results were seen at 24 h (data not shown).

The peak analgesic effect, measured by the peak pain relief score within the first 6 h after dosing, was similar between etoricoxib and oxycodone/acetaminophen (Table 2). Both etoricoxib and oxycodone/acetaminophen were associated with higher peak pain relief scores than placebo (P < 0.001 for both comparisons).

The duration of analgesic effect, indicated by the median time to first use of opioid medication, was significantly longer for etoricoxib compared with oxycodone/acetaminophen (P < 0.001). Both etoricoxib and oxycodone/acetaminophen had a significantly longer duration of analgesic effect compared with placebo (P < 0.001 for both comparisons) (Table 2).

Within the first 6 h postdose, a smaller percentage of patients treated with etoricoxib required rescue analgesia compared with those treated with oxycodone/acetaminophen (P < 0.01) (Table 2). Compared with placebo, a smaller percentage of patients treated with etoricoxib or oxycodone/acetaminophen required rescue analgesia (P < 0.001 for etoricoxib; P < 0.01 for oxycodone/acetaminophen comparison). Within the first 24 h postdose, similar results were found, with the exception of patients treated with oxycodone/acetaminophen compared with those treated with placebo, for whom at 24 h there was no significant difference (Table 2).

The amount of rescue analgesia used over 6 h postdose for patients treated with etoricoxib was significantly less in the etoricoxib group than in the oxycodone/acetaminophen group (P < 0.01) (Table 2). The amount of rescue analgesia used over 24 h was also significantly less in the etoricoxib group compared with the placebo group (P < 0.001) and in the oxycodone/acetaminophen group compared with the placebo group (P < 0.01). Over the 24-h period, etoricoxib-treated patients took less rescue analgesia than the oxycodone/acetaminophen-treated patients (P < 0.001) and placebo-treated patients (P < 0.001); however, there was no significant difference between the oxycodone/acetaminophen and placebo groups.

Overall, more AEs were reported in the oxycodone/acetaminophen group compared with the etoricoxib and placebo groups (P < 0.001 for both comparisons) (Table 4). For other prespecified comparisons, significantly more drug-related clinical AEs occurred in patients treated with oxycodone/acetaminophen than in patients treated with etoricoxib or placebo (Table 4). No serious AE was reported in any group. The incidence of AEs was similar between etoricoxib and placebo.

View this table: [in this window] [in a new window]   Table 4. Adverse Events Summary and Specific Adverse Events with an Incidence of 5.0% in Any Treatment Group

	Discussion

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Opioid analgesics are standard treatment for acute postoperative pain (12,19). Among hospitalized patients, parenteral opioids such as patient-controlled analgesia with morphine can be used for pain. In the outpatient setting, however, patients must rely on oral analgesics to control postoperative pain. Various opioid analgesics in combination with acetaminophen are available for oral administration, such as oxycodone, hydrocodone, and codeine.

The postoperative dental impaction pain model is a well validated and widely accepted model for assessing the efficacy of analgesics in acute pain because of its reproducibility, high precision, accuracy, and sensitivity in differentiating the efficacy of two drugs (12). Oxycodone/acetaminophen has been shown to be effective in acute pain studies in the dental impaction model (14,15). In this postoperative pain study, 120 mg of etoricoxib, a specific inhibitor of COX-2, was compared with oxycodone/acetaminophen 10/650 mg, the largest initial dose used for acute pain. The overall analgesic effect for etoricoxib-treated patients was superior to that for oxycodone/acetaminophen-treated patients, as measured by TOPAR6, the primary efficacy end-point. The superior overall analgesic effect of etoricoxib was supported by analysis of SPID6 results. Although the percentage of responders for etoricoxib based on PGART at 6 and 24 hours was similar to that for oxycodone/acetaminophen, the actual numeric PGART scores for the former were statistically superior to those for the latter, reflecting a larger percentage of etoricoxib patients with an excellent response than oxycodone/acetaminophen patients (28.6% versus 9.3% at 6 hours postdose; 32.3% versus 10.0% at 24 hours postdose) (Table 3).

Determining the number of patients who achieve at least 50% TOPAR over six hours is now considered to be a reasonable measure of comparative analgesic efficacy in acute postoperative pain trials (20). Meta-analyses of single doses of celecoxib 200 mg (21), valdecoxib 20 mg (22), and rofecoxib 50 mg (23) in acute postoperative pain have demonstrated that these specific COX-2 inhibitors provide at least 50% maximum TOPAR over six hours in 40%–68% of treated patients. In this study, the percentage of patients who achieved 50% maximum TOPAR over six hours was 71% (71 of 100) for the etoricoxib-treated group, 53% (53 of 100) for the oxycodone/acetaminophen group, and 12% (3 of 25) for the placebo group. To maintain consistency with other efficacy analyses performed in this study, we determined ORs adjusted for baseline pain intensity for 50% of maximum TOPAR over six hours: for patients treated with etoricoxib compared with oxycodone/acetaminophen, the OR was 2.17 (95% CI, 1.21–3.90); for etoricoxib compared with placebo, the OR was 18.27 (95% CI, 5.06–65.99); and for oxycodone/acetaminophen compared with placebo, the OR was 8.40 (95% CI, 2.36–29.96).

In addition to overall analgesic effect, other important characteristics of a pain medication include how quickly the drug exerts its analgesic effect, the maximum analgesic effect of the medication regardless of how fast it works, and how long the drug exerts its effects. Opioid analgesics generally have a rapid onset of analgesic effect; this was confirmed in the current study, because oxycodone/acetaminophen had a median onset of 23.5 minutes. Although oxycodone/acetaminophen demonstrated a significantly more rapid onset of pain relief than etoricoxib, the latter also exhibited a rapid median onset of 29.0 minutes. Peak analgesic effects of both drugs were similar. Analysis of the duration of analgesic effect, measured by time to first use of rescue medication, showed that etoricoxib provided a significantly longer duration of pain relief than oxycodone/acetaminophen. For patients treated with etoricoxib, the median duration was longer than 24 hours, which is consistent with the long half-life of etoricoxib and permits once-daily dosing, compared with 7.4 hours for oxycodone/acetaminophen, a drug that requires multiple dosing over 24 hours.

The recommended dosing interval for oxycodone/acetaminophen is every 6 hours (16). Therefore, this study focused on the analgesic efficacy comparison over the first 6 hours after dosing rather than over the entire study duration of 24 hours. Because oxycodone/acetaminophen is given as early as 4 hours after the previous dose in some postoperative settings, a post hoc analysis focusing on the 4-hour comparison was also conducted. The overall analgesic effect as assessed by TOPAR4 and SPID4 also supported the superior overall analgesic efficacy of etoricoxib over oxycodone/acetaminophen.

Because of side effects associated with opioid analgesics, such as nausea, vomiting, dizziness, somnolence, urinary retention, and constipation, reduction of the need for opioid analgesia is desirable (13,24). In some instances, these side effects contribute to delays in discharge of postsurgical patients from the hospital or clinic (25). In this study of postoperative dental pain, a smaller percentage of patients using etoricoxib required additional opioid analgesia during the first 6- and 24-hour interval. Etoricoxib-treated patients demonstrated a small but significant reduction in the amount of opioid rescue medication consumed by patients within the first 6- and 24-hour interval. Although it is likely that other NSAIDs given in the postoperative setting may also reduce rescue opioid consumption, the lack of antiplatelet activity of etoricoxib may reduce the risk of perioperative bleeding.

The use of oxycodone/acetaminophen 10/650 mg as the initial postoperative drug was associated with more frequent side effects and drug-related side effects. The incidences of nausea and vomiting experienced by patients treated with oxycodone/acetaminophen were significantly more frequent than for patients who received etoricoxib. Although patients receiving placebo used at least as much opioid analgesia as those in the oxycodone/acetaminophen group, incidences of nausea and vomiting were still more frequent in the oxycodone/acetaminophen group. Therefore, frequent AEs in the oxycodone/acetaminophen group appear to have been influenced by the initial use of this opioid, possibly compounded by subsequent consumption of rescue opioid medication.

In summary, this study demonstrated that the overall analgesic efficacy over 6 hours of a single dose of etoricoxib 120 mg was superior to that with a single dose of oxycodone/acetaminophen 10/650 mg in the treatment of acute postsurgical dental pain. Etoricoxib had a rapid onset of action and demonstrated a peak analgesic effect similar to and a duration of analgesic effect longer than oxycodone/acetaminophen. The administration of etoricoxib reduced the need for rescue opioid analgesia compared with oxycodone/acetaminophen. Etoricoxib was generally well tolerated and was associated with significantly less nausea and vomiting compared with oxycodone/acetaminophen. The results of this study confirm that etoricoxib is an effective and generally well tolerated once-daily analgesic therapy for patients with acute postoperative dental pain.

	Acknowledgments

 
Supported by Merck & Co., Inc.

The authors acknowledge the contributions of the following individuals in the execution of this study and in the preparation of this manuscript: Frank Bonasso, DDS, Lily Chen, Barbara Hernandez, R. Dean Jasper, DDS, Henry W. Marcantoni, DMD, PhD, Tamara Montano, Yuki Morris, Lisa Mucciola, MS, Francisco Perez, DMD, MSD, Steven J. Perkins, DDS, Carol Skalky, Denise Stek, John Yates, MD, Robin Hernandez, and Alicia Bauman.

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This Article Abstract Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Chang, D. J. Articles by Geba, G. P. Search for Related Content PubMed PubMed Citation Articles by Chang, D. J. Articles by Geba, G. P. Related Collections Pain Pharmacology