Analgesic efficacy of rofecoxib compared with codeine/acetaminophen using a model of acute dental pain

Study design Patients (N = 390) experiencing moderate or severe pain postextraction of 2 or more third molars, with at least 1 mandibular impaction, were randomized to placebo (n = 30), rofecoxib (n = 180), or codeine/acetaminophen 60/600 mg (n = 180). Time to confirmed perceptible pain relief, and patient evaluations of pain intensity, pain relief, and global assessments were recorded. Results For total pain relief over 6 hours (primary end point), rofecoxib was superior to codeine/acetaminophen (15.5 vs 10.7; P < .001). Rofecoxib was statistically significantly superior to codeine/acetaminophen with respect to TOPAR4, patient global assessment, peak pain relief, and duration of analgesic effect. Median onset of analgesia was similar for both drugs. The codeine/acetaminophen group had more patients with 1 or more adverse events. Conclusion Rofecoxib provided superior analgesic efficacy compared with codeine/acetaminophen with fewer gastrointestinal and nervous system adverse events. Rofecoxib, a member of the selective cyclo-oxygenase-2 (COX-2) inhibitor class, has been shown to have efficacy in a variety of models of acute pain, including postoperative dental pain, 1 postorthopedic surgery pain, 2 and primary dysmenorrhea. 3 The components of analgesic efficacy measured by these models included global assessment of pain relief and onset, peak, and duration of relief. In these models, rofecoxib 50 mg showed analgesic efficacy similar to that of maximum single analgesic doses of comparator nonsteroidal anti-inflammatory drugs (NSAIDs), but with a more rapid onset and a duration of action longer than that of ibuprofen. 1 Rofecoxib has also been shown to be as effective as non-selective NSAIDs in the treatment of pain associated with osteoarthritis. 4-6 Compared with nonselective NSAIDs, rofecoxib has demonstrated superior gastrointestinal safety. Clinical trials involving more than 1500 patients with osteoarthritis demonstrated that rofecoxib was associated with a decreased risk of endoscopically diagnosed ulcers after 6 months of treatment compared with nonselective NSAIDs. 7,8 In a pooled analysis of more than 5400 patients with osteoarthritis, 9 a higher incidence of gastroduodenal perforations, ulcers, or upper gastrointestinal bleeds was seen among those treated with nonselective NSAIDs compared with patients treated with rofecoxib. A recent study of more than 8000 patients with rheumatoid arthritis demonstrated a higher rate of endoscopically proven gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, or symptomatic gastroduodenal ulcers among naproxen-treated patients compared with rofecoxib. 10 We conducted a randomized, single-dose, placebo-controlled study to examine the analgesic efficacy of rofecoxib 50 mg in treatment of acute pain following molar extraction. We compared the analgesic efficacy of a single oral dose of rofecoxib 50 mg with the combination of acetaminophen 600 mg with the maximum single dose of codeine 60 mg and with placebo in individuals with moderate to severe pain following dental surgery. This study used the well-validated postoperative dental pain model of acute pain. 11,12 The Food and Drug Administration's Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee voted at their combined meeting in February 2005 that Merck & Co, Inc, could consider reintroducing rofecoxib to the United States market with certain restrictions to its use. 13 Patients and methods Study design This randomized, double-blind, placebo- and active-comparator-controlled, parallel-group study compared single doses of rofecoxib 50 mg, codeine/acetaminophen 60/600 mg, and placebo. The doses of medication were selected based on the product labeling. 14,15 The study consisted of a prestudy visit, a treatment visit (dental surgery and randomization), and a poststudy visit occurring 5 to 10 days after surgery. The study protocol and informed consent were approved by Quorum Institutional Review Board (Olympia, Wash). Prior to enrollment in the study, all patients provided written informed consent. The study was completed before September 30, 2004, when Merck & Co, Inc, announced the voluntary worldwide withdrawal of rofecoxib from the market. Eligibility and exclusion criteria Patients were eligible for enrollment if they were 16 years of age or older and had been scheduled to undergo removal of 2 or more third molars, at least one of which was partially embedded in the mandibular bone. Exclusion criteria included allergic reactions or intolerance to aspirin, ibuprofen, indomethacin, other NSAIDs, rofecoxib, codeine, acetaminophen, or hydrocodone bitartrate; concomitant use of tricyclic antidepressants, opioid analgesics, 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 the results of the study or pose additional risk to the patients. Intraoperative anesthetics allowed included lidocaine, methohexital sodium, fentanyl, and nitrous oxide. Four oral surgeons from 2 sites were involved in performing the procedures on the patients. Study conduct Patients who reported moderate or severe pain after the molar extraction surgery were eligible for randomization to rofecoxib 50 mg, codeine/acetaminophen 60/600 mg, or placebo in a 6:6:1 ratio. Study medication was administered to the patient as a single dose in a double-blind fashion, using matching placebo. Randomization was stratified based on the baseline pain intensity rating of moderate or severe. Rescue analgesic medication (hydrocodone/acetaminophen 5/500 mg) was available to patients who did not achieve adequate pain relief after receiving study medication. Patients were encouraged not to use rescue medication during the first 90 minutes after study medication dosing. End points Standard end points recommended in guidelines for the evaluation of analgesic medications were used in the study. 11,12 Overall analgesic effect was primarily assessed by total pain relief (TOPAR), as determined by the sum of time-weighted pain relief scores over 6 hours (TOPAR6). The primary endpoint was TOPAR6. Other endpoints in the study included patient global assessment of response to therapy (PGART) at 6 hours and at 24 hours (overall analgesic effect), time to pain relief using stopwatches (onset of analgesic effect), peak pain relief during the first 6 hours after dosing (peak analgesic effect), time to rescue medication (duration of analgesic effect), proportion of patients requiring rescue analgesia, and incidence of adverse events (AEs), especially nausea. Efficacy assessments Patients recorded their pain symptoms at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, and 24 hours after administration of study medication. Pain intensity was recorded on a 4-point scale (0 = none, 1 = slight, 2 = moderate, and 3 = severe). Pain relief was recorded on a 5-point scale (0 = none, 1 = a little, 2 = some, 3 = a lot, and 4 = complete). PGART was assessed at 6 and 24 hours (0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent). Two stopwatches were started at the time of study drug administration. When perceptible pain relief was achieved, the patient stopped the first stopwatch; when meaningful pain relief was attained, 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 had meaningful pain relief (the second stopwatch time). 16 If perceptible pain relief was obtained without associated meaningful pain relief, a censored value of 4 hours was used in the analysis of the stopwatch times. Patients were required to remain at the study site for a total of 6 hours after dosing of the study medication. Self-assessments of efficacy at 7, 8, 12, and 24 hours were performed after the patients had been discharged from the study site. Patients who used any rescue or supplemental analgesic medication recorded the date, time, and amount taken. Just prior to taking the first dose of rescue medication, patients assessed their pain intensity, pain relief, and PGART. No further efficacy measurements were required after the rescue medication was taken. Safety assessments The safety of the study medications was determined by physical examination, vital signs, laboratory testing, and spontaneous reporting of any adverse experiences. Statistical evaluation Efficacy analyses were based on an intention-to-treat approach; all patients with a baseline assessment and at least one measurement after medication dosing were included in the analysis. The primary objective of the study was the comparison of TOPAR6 between rofecoxib and codeine/acetaminophen. If the true underlying difference was 3.44 points favoring rofecoxib, 180 patients per group provided 86% power to declare that rofecoxib was superior to codeine/acetaminophen. Pairwise treatment comparisons for TOPAR6, PGART, and peak pain relief were analyzed using an analysis of variance model with factors for treatment group, study center, and baseline pain intensity. A logistic regression model with factors for treatment group, study center, and baseline pain intensity was used in the analysis of the percentage of patients taking rescue medication and PGART in terms of responders (good, very good, or excellent) versus nonresponders (fair or poor). For pain relief, pain intensity, and PGART, missing evaluations were estimated by carrying forward the last available observation. Analyses of stopwatch times and time to rescue medication were performed using Kaplan-Meier time-to-event estimates with corresponding Wilcoxon statistics. All randomized patients were included in the evaluation of safety. Fisher's exact test was used to compare the treatment groups in terms of incidence of clinical adverse experiences. For all efficacy and safety comparisons, differences were considered to be statistically significant at P less than .05 (2-tailed). Results A total of 390 patients were enrolled; 180 received rofecoxib, 180 received codeine/acetaminophen, and 30 received placebo. The baseline characteristics among the treatment groups were similar ( Table I ). Overall, 52.6% were female; 96.2% were white, 1.8% Hispanic, 0.8% of mixed racial origin, 0.5% Polynesian, 0.5% Asian Americans, and 0.3% American Indian. The mean age was 19.1 years. At baseline, 59.5% reported moderate pain after surgery; 40.5% reported severe pain. One patient from the rofecoxib group was discontinued because of being lost to follow up. Efficacy Overall analgesic effect Overall analgesic effect, as measured by the primary endpoint TOPAR6, was significantly greater for rofecoxib than for codeine/acetaminophen ( P < .001) and placebo ( P < .001); TOPAR6 was greater for codeine/acetaminophen than placebo ( P < .010) ( Table II ). The mean pain relief scores over a 24-hour period are shown in Fig 1 . Based on PGART at 6 hours, a greater percentage of patients responded to rofecoxib compared with codeine/acetaminophen (85.0% vs 68.2%, P < .001) ( Fig 2 ). Fewer patients on placebo (36.7%) were responders compared with rofecoxib ( P < .001) and codeine/acetaminophen ( P < .010). The mean PGART scores at 6 hours were statistically significantly higher for patients on rofecoxib than for patients on codeine/acetaminophen ( P < .001) and placebo ( P < .001) ( Table II ); patients treated with codeine/acetaminophen had a higher mean score than placebo ( P < .010). Results were similar for the percentage of responders and mean PGART scores at 24 hours (data not shown). To confirm overall analgesic efficacy at 4 hours, a post hoc analysis of total pain relief over 4 hours (TOPAR4) was performed, using the same statistical methods as was used for TOPAR6. TOPAR4 was determined by summing the time-weighted pain relief scores over 4 hours. TOPAR4 for rofecoxib was 9.6 (95% confidence interval [CI]: 9.0, 10.2) and was significantly greater ( P < .001) than codeine/acetaminophen, which was 7.6 (95% CI: 7.0, 8.2). TOPAR4 for both rofecoxib and oxycodone were significantly greater ( P < .001) than for placebo (4.1, 95% CI: 2.6, 5.6). Onset of analgesic effect Evaluation of onset of analgesic effect, as determined by time to confirmed perceptible pain relief ( Table II ), demonstrated no significant differences between rofecoxib (27.0 minutes) and codeine/acetaminophen (24.6 minutes). The onset was significantly faster ( P < .001) for both rofecoxib and codeine/acetaminophen compared with placebo (>240 minutes). Peak analgesic effect The peak analgesic effect of rofecoxib, as assessed by peak pain relief scores during the first 6 hours, was significantly greater than that of codeine/acetaminophen ( P < .001) ( Table II ). Both medications had statistically significantly higher peak pain relief scores than placebo ( P < .001). Duration of analgesic effect Fewer patients on rofecoxib required rescue medication compared with codeine/acetaminophen and placebo. Approximately 73%, 86%, and 43% of patients treated with placebo, codeine/acetaminophen, and rofecoxib, respectively, used rescue analgesia during the 24-hour period after study medication dosing ( P < .001, rofecoxib vs codeine/acetaminophen and placebo; no significant difference between codeine/acetaminophen and placebo). The median time to rescue medication after dosing was significantly longer for rofecoxib (>24 hours) than for codeine/acetaminophen (6.5 hours), and placebo (3.2 hours) ( Table II ). This is consistent with the longer duration of action of rofecoxib. Safety profile No severe or unexpected AEs were reported, and no patients withdrew from the study because of an AE. One or more adverse experiences were reported in 22.2%, 35.0%, and 46.7% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively, with significantly more events in the codeine/acetaminophen group compared with rofecoxib ( P < .05) and placebo ( P < .01). There was no significant difference between the codeine/acetaminophen and placebo-treated groups with respect to the overall incidence of AEs. The most common AE was nausea, found in 7.2%, 13.9%, and 10.0% of rofecoxib, codeine/acetaminophen, and placebo patients, respectively. Other common gastrointestinal or nervous system AEs included vomiting (occurring in 5.6%, 13.9%, and 6.7% of rofecoxib, codeine/acetaminophen, and placebo patients, respectively); headache (4.4%, 7.8%, and 20.0%); and dizziness (0.0%, 3.9%, and 0.0%). Although approximately half as many patients treated with rofecoxib experienced nausea compared with those treated with codeine/acetaminophen, this difference was marginally nonsignificant ( P = .058). For both rofecoxib and codeine/acetaminophen, there were no significant differences compared with placebo for nausea. Compared with codeine/acetaminophen, fewer patients on rofecoxib experienced vomiting ( P < .05), and dizziness ( P < .05). There was no significant difference in the percentage of patients with vomiting between rofecoxib and placebo. Although numerically fewer patients treated with placebo experienced vomiting in comparison to codeine/acetaminophen, this difference was not statistically significant. None of the other between-group differences for gastrointestinal and nervous system AEs achieved statistical significance ( P ≥ .05). No serious laboratory AEs occurred in this study. Discussion This study demonstrated that a single oral dose of rofecoxib 50 mg, the recommended dose for the treatment of acute pain, provided analgesic efficacy superior to that of the acetaminophen 600 mg in fixed formulation with the maximum single dose of codeine 60 mg. The greater analgesic efficacy of rofecoxib was achieved with respect to overall effect, peak effect, and duration of effect. The onset of effect was rapid and similar for both drugs. Codeine is considered to be a relatively safe oral analgesic with a low abuse potential. Gastrointestinal and nervous system side effects, however, are frequently associated with the medication. The common occurrence of these AEs was underscored in the present study: higher incidences of nausea, vomiting, and lightheadedness were noted among patients taking only a single dose of codeine/acetaminophen in comparison with patients treated with rofecoxib. This study challenges the common perception that opioid analgesics are more effective for pain than NSAIDs. The results of the study demonstrate that the overall analgesic efficacy of rofecoxib 50 mg over 6 hours, as assessed by TOPAR6 and PGART at 6 hours, was superior to codeine/acetaminophen 60/600 mg. At 4 hours, the earliest time at which codeine can be redosed, TOPAR4 was greater for rofecoxib than for codeine/acetaminophen. Codeine/acetaminophen, like many immediate-release opioid analgesics, is perceived to have a rapid onset of action, yet in this study rofecoxib had an onset of analgesic effect as rapid as the opioid combination drug. The rapid onset of analgesia is consistent with prior studies of rofecoxib in the postoperative dental-impaction pain model. 1,17 The peak effect, which is the maximum analgesic effect provided by a medication regardless of time, also showed superiority for rofecoxib. The duration of analgesic effect was assessed by time to rescue analgesia medication and was significantly longer for rofecoxib than codeine/acetaminophen, consistent with the longer half-life (approximately 17 hours) of rofecoxib. Patients on rofecoxib had a lower incidence of one or more AEs as well as nausea, vomiting, and lightheadedness compared with patients treated with codeine/acetaminophen. These parameters are important since overall efficacy, rapid onset of action, long duration of analgesic effect, and low incidence of side effect are desired characteristics of pain medications. The efficacy of a single dose of rofecoxib has been demonstrated in previous postoperative dental pain investigations. 1,17 This study confirms the effectiveness of rofecoxib in acute postoperative dental pain 18-22 and further supports the superior efficacy of COX-2 selective inhibitors compared to oral opioid analgesics in the acute pain model. 18,19,21 Other studies have compared the efficacy of non-COX-2 selective NSAIDs to codeine with acetaminophen in the acute dental-impaction pain model with variable results. Compared with codeine 60 mg with 600 mg or 650 mg of acetaminophen, oral ketorolac 10 mg has been shown to be superior over a 6-hour time period 23 ; the 4-hour interval was not evaluated. The results of flurbiprofen 50 mg and 100 mg have not been consistent. Two studies have demonstrated flurbiprofen 100 mg to be more effective than codeine 60 mg with acetaminophen 600 mg or 650 mg over 6 hours 24,25 ; 2 other studies have shown no statistical difference between the drugs over a 4-hour or 6-hour interval. 26,27 Examining the efficacy of diflunisal 500 mg and 1000 mg over 4 hours, Forbes et al 28 concluded that both doses were similar in efficacy compared with codeine/acetaminophen 60/600 mg. When the 12-hour effect was investigated, both doses of diflunisal were superior to codeine/acetaminophen. Ibuprofen 400 mg was significantly more effective than codeine/acetaminophen 60/600 mg over 6 hours 29 but was similar to codeine/acetaminophen 60/600 mg and codeine/aspirin 60/650 over the shorter time-period of 4 hours. 11 A study of meclofenamate sodium 100 mg demonstrated similar efficacy compared with codeine/acetaminophen 60/600 mg over 6 hours. 30 The lack of a consistently superior effect of previously studied NSAIDs compared to codeine/acetaminophen may have several possible explanations, including a slower onset of action or lower peak effect of these NSAIDs compared with rofecoxib. Due to small sample sizes (typical number of patients ranged from 20 to 40), these studies may not have had adequate power to detect clinically significant differences. Whereas many of the studies showed a numerical superiority of NSAIDs over the opioid analgesics, some of them did not achieve statistical significance. Another explanation may be the time frame in which efficacy was assessed. Some studies examined the effect over 4 hours while others used a 6-hour or 12-hour interval. Because the NSAIDs studied have a longer effect than codeine/acetaminophen, the longer assessment period would be more likely to favor a superior effect for the NSAIDs. Codeine is frequently prescribed every 6 hours or 4 times per day; consequently, we assessed the 6-hour TOPAR as the primary end point, which demonstrated greater efficacy for rofecoxib. However, in contrast to other NSAID studies, the 4-hour effect using TOPAR4 demonstrated superiority of rofecoxib over codeine/acetaminophen as well. Studies comparing nonselective NSAIDs to noncodeine opioid analgesics are limited. Fricke et al 31 demonstrated that ketorolac 10 mg was more effective than hydrocodone/acetaminophen 10/1000 mg over 6 hours. Compared with propoxyphene 100 mg, diflunisal 500 mg and 1000 mg were superior in efficacy over 12 hours, 28 although only the 1000-mg dose was superior to the combination of propoxyphene/acetaminophen 100/650 mg over the same time. More recently, 2 tablets of the fixed combination of hydrocodone/ibuprofen 7.5/200 mg were shown to be superior in analgesic effect compared with codeine/acetaminophen 60/600 mg over 6 hours. 32 Rofecoxib has been shown to provide efficacy in acute pain similar to that of dual COX-1 and COX-2 inhibiting NSAIDs such as ibuprofen and naproxen. 1-3 Rofecoxib, however, has fewer gastrointestinal side effects than nonselective NSAIDs such as ibuprofen, naproxen, diclofenac, and nabumetone, 7-10 presumably owing to its lack of inhibition of COX-1. The acute postoperative dental-impaction pain model is an accepted, sensitive, and validated model for assessing the analgesic efficacy of drugs in humans. 11,12 The postoperative dental pain model has been demonstrated to be a good indicator for drug response in other acute nondental pain models. 33 In the clinical setting, patients suffering acute pain are frequently treated with opioids such as codeine combinations because of their perceived superior efficacy over NSAIDs and coxibs. In acute pain settings where inflammation significantly contributes to the intensity of pain, as in soft tissue injury or postoperative pain, the combined anti-inflammatory and analgesic properties of rofecoxib and other drugs that inhibit COX-2 may provide added benefit to patients over opioids. Conclusion In summary, this study demonstrated that a single dose of rofecoxib 50 mg had superior analgesic effect compared with codeine/acetaminophen 60/600 mg. 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