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Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: A randomized, placebo-controlled clinical trial
CLINICAL THERAPEUTICSYVOL. 24, NO. 4,2002
Comparison of the Analgesic Efficacy of Rofecoxib and Enteric-Coated Diclofenac Sodium in the Treatment of Postoperative Dental Pain: A Randomized, Placebo-Controlled Clinical Trial David J. Chang, MD,’ Paul J. Desjardins, DMD, PhD,2 Erluo Chen, MPH,, Adam B. Polis, MA,’ Mary McAvoy, MMS,’ Sandra H. Mockoviuk, BS,l and Gregory I? Geba, MD’ ‘Merck & Co, Inc, West Point, Pennsylvania, and 2SCIREX Corporation, Austin, Texas, and Department of Oral Pathology, Biology and Diagnostic Sciences, University of Medicine and Dentistry, New Jersey Dental School, Newark, New Jersey
ABSTRACT Background: Rofecoxib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. Objective: The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. Methods: In this double-blind, placebo- and active comparator-controlled, parallelgroup study, patients experiencing moderate to severe pain after the surgical extraction of 22 third molars were randomized to receive a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPARS) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. Results: A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% exAccepted
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February 28, 2002.
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D.J. CHANG ET AL.
perienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with entericcoated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and ~4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (~24 hours vs 1 hour and 37 minutes). Entericcoated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, al-
though the rofecoxib group had a significantly lower incidence of clinical and drugrelated adverse events than the entericcoated diclofenac sodium group. Conclusions: A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours. Key words: rofecoxib, diclofenac, cyclooxygenase-2 inhibitor, nonsteroidal antiinflammatory drug, postoperative dental pain, oral surgery, analgesic. (C/in Thel: 2002;24:490-503)
INTRODUCTION Rofecoxib is a selective cyclooxygenase2 inhibitor with demonstrated efficacy in acute analgesic models of postoperative dental pain,“2 postorthopedic surgery pain3 and primary dysmenorrhea.4 In the postoperative dental impaction pain model, rofecoxib 50 mg is similar in overall analgesic efficacy to maximum single analgesic doses of ibuprofen and naproxen sodium,“2 superior to celecoxib 200 mg,5 and superior to codeine 60 mg with acetaminophen 600 mg.6 However, based on a MEDLINE search (1966 through February 2002) using the terms rofecoxib and diclofenac, no studies of acute pain management have compared the analgesic efficacy of rofecoxib with diclofenac, the most commonly prescribed nonsteroidal anti-inflammatory drug (NSAID) world-
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wide.7*8 Although indicated for the treatment of the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis in the United States,9 oral enteric-coated diclofenac sodium is also effective in a variety of acute pain settings such as postoperative oral surgery pain, lo-l4 dysmenorrhea,15*16 and acute migraine.i7 The objectives of this investigation were to compare the analgesic effects of a single dose of rofecoxib 50 mg and a single dose of enteric-coated diclofenac sodium 50 mg over an &hour period, and to compare a single dose of rofecoxib 50 mg and 3 doses of enteric-coated diclofenac sodium 50 mg over a 24-hour period, using a standard, validated postoperative dental pain model. l8 Immediate-release diclofenac potassium, while available in the United States, is not widely available or prescribed in other countries8; therefore, it was not selected as the comparator agent in this study.
PATIENTS
AND METHODS
Patients Patients were eligible to participate in the study if they were healthy males or females, 216 years of age, and scheduled to undergo surgical removal of 22 third molars, at least 1 of which was partially embedded in the mandibular bone. Standard intraoperative anesthesia was allowed, including lidocaine, midazolam, fentanyl, and nitrous oxide. Only participants experiencing moderate to severe pain on a categorical verbal pain scale were randomized. Reasons for exclusion included allergic reactions or intolerance to aspirin, NSAIDs, acetaminophen, or hydrocodone bitartrate; concomitant use of tricyclic an-
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tidepressants, 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 that might confound the results of the study or pose additional risk to the patients. All women were required to have negative results on urine pregnancy testing. Before enrollment in the study, all patients provided written informed consent on a form approved by an institutional review board. Study Design This randomized, double-blind, placeboand active comparator-controlled, parallelgroup study was conducted at 4 centers. All patients were enrolled over a 4week period. Following third molar extraction surgery, patients who reported moderate or severe pain were eligible for randomization to a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given orally every 8 hours), or placebo in a 2:2: 1 ratio. The rofecoxib dose used is the indicated dose for analgesia.19 Prior studies have shown the effectiveness of diclofenac sodium 50 mg in the acute dental pain model.10-13 The dosing frequency of diclofenac sodium 50 mg every 8 hours was consistent with the recommended prescribing information, which is 50 mg twice daily or 3 times daily (TID) for osteoarthritis and 50 mg TID or 4 times daily for rheumatoid arthritis.9 When used for analgesia, the recommended starting dose for the immediate-release formulation of diclofenac is 50 mg TID.9 Randomization was stratified based on the baseline pain intensity of moderate or severe on a categorical verbal pain scale using a
D.J. CHANG ET AL.
computer-generated allocation schedule. The study medications were administered to patients in a double-dummy fashion. To maintain blinding, rofecoxib or its matching placebo was administered at baseline to all patients; diclofenac sodium or its matching placebo was given at baseline, 8 hours, and 16 hours to all patients. After study medication was taken, patients rated pain intensity, pain relief, and global assessments at 17 prespecified times over a 24-hour period. Patients were required to remain at the study site for 24 hours after the initial dosing of the study medication. Patients who experienced inadequate pain relief were allowed to take rescue analgesic medication (hydrocodone/ acetaminophen 5/500 mg) at any time.
Efficacy Assessments Patients recorded their pain intensity and pain relief at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, and 24 hours after administration of the initial dose of study medication. Standard and established pain rating scales for postoperative dental pain were used.‘* Pain intensity was recorded on a 4-point categorical verbal scale (0 = none, 1 = slight, 2 = moderate, and 3 = severe); pain relief was recorded on a 5-point categorical verbal scale (0 = none, 1 = a little, 2 = some, 3 = a lot, and 4 = complete). Patients provided global assessments at 8 hours and 24 hours (0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent), with nonresponders including patients with a poor or fair rating and responders including patients with good, very good, or excellent rating. The overall analgesic efficacy was determined by total pain relief over 8 hours (TOPARS; range 0 to 32) and 24 hours (TOPAR24; range 0 to 96) and patient
global assessments at 8 hours and 24 hours. TOPARS and TOPAR were derived by summing time-weighted pain relief scores over g-hour and 24-hour periods, respectively. Other end points in the study included onset of analgesic effect, peak analgesic effect, duration of analgesic effect, and percentage of patients requiring rescue medication within 8 and 24 hours. Onset of analgesic effect was determined using 2 stopwatches, which were started at the time of the administration of the initial dose of study drug. 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).2o If perceptible pain relief was obtained without associated meaningful pain relief, a censored value of 4 hours was used. Peak analgesic effect was the maximum pain relief achieved during the first 8 hours. The duration of analgesic effect was determined by calculating the median time to rescue medication use. Adverse events were determined based on spontaneous reporting by patients. If patients required rescue analgesia, they recorded their pain intensity, pain relief, and global assessments just prior to taking the first rescue medication.
Safety Assessments The safety of the study medications was determined by limited physical examination, vital signs, and spontaneous reporting of any adverse experiences. After the occurrence of an adverse experience but prior
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to unblinding, investigators determined the adverse experience was related to study drug. Events that were considered the investigator to be possibly, probably, definitely drug-related were recorded drug-related adverse experiences.
if the by or as
Statistical Analysis The primary objective of the study was to compare TOPARS of rofecoxib and enteric-coated diclofenac sodium. Based on estimates from prior rofecoxib dental pain studies’,2,5,6 and enteric-coated diclofenac sodium dental pain studies,iO,’ 1 the sample size of 120 patients per group was calculated to provide 92% power to declare that rofecoxib was superior (P < 0.05) to diclofenac. Efficacy analyses were based on a modified intent-to-treat approach. This approach included all patients treated with a baseline assessment and at least 1 measurement after the initial medication dosing. For pain intensity, pain relief, and patient global assessment, missing values were estimated by carrying forward the last available observation. If rescue medication was taken, the recorded assessments (pain intensity, pain relief, and patient global assessment) at the time of first rescue analgesia use were carried forward. Pairwise treatment comparisons for TOPAR8, TOPAR24, patient global assessment scores at 8 and 24 hours, and peak pain relief were analyzed using an analysis of variance model with factors for treatment group, baseline pain intensity, and study center. A logistic regression model with factors for treatment group, baseline pain intensity, and study center was used in the analysis of the percentage of patients taking rescue medication and patient global assessment in terms of responders (good, very good, or excel494
lent) versus nonresponders (fair or poor). Analysis of time to confirmed perceptible pain relief and time to first rescue medication were performed using Kaplan-Meier time-to-event estimate with corresponding Wilcoxon statistics. All randomized and treated patients were included in the assessment of safety. The Fisher 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 < 0.05 (2-tailed).
RESULTS A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline characteristics among the treatment groups were generally similar with respect to sex, race, age, and baseline pain intensity (Table I). Overall, 61.3% (187 of 305) had moderate baseline pain and 38.7% (118 of 305) had severe baseline pain.
EJGcacy Overall Analgesic Effect The overall analgesic effect over 8 hours, as measured by the primary end point TOPAR8, was significantly greater for a single dose of rofecoxib 50 mg than for a single dose of diclofenac sodium 50 mg (20.5 vs 8.2; P < 0.001) and placebo (20.5 vs 5.9; P < 0.001) (Table II). For the 24hour assessment TOPAR24, a single dose of rofecoxib 50 mg provided significantly greater pain relief than 3 doses of diclofenac sodium 50 mg (64.1 vs 25.1; P c 0.001) or placebo (64.1 vs 19.2; PC 0.001). The pain relief scores over a 24-hour period are shown in Figure 1. At every time
D.J. CHANG ET AL.
Table I. Baseline characteristics,
by treatment Rofecoxib
group.* Diclofenac
Sodium
(50 mg) (n = 121)
(50 mg q8b) (n = 121)
Placebo (n = 63)
Sex, no. (%) Male Female
62 (51.2) 59 (48.8)
48 (39.7) 73 (60.3)
33 (52.4) 30 (47.6)
Race, no. (%) White Other Black Asian Multiracial
65 34 18 2 2
77 23 15 4 2
45 (7 1.4) 7 (11.1) 7 (11.1) l(l.6) 3 (4.8)
Age, y (mean + SD)
24.2 f 5.1
22.8 + 5.0
22.8 + 4.4
Baseline pain intensity,’ no. (%) Moderate Severe
73 (60.3) 48 (39.7)
76 (62.8) 45 (37.2)
38 (60.3) 25 (39.7)
(53.7) (28.1) (14.9) (1.7) (1.7)
(63.6) (19.0) (12.4) (3.3) (1.7)
*Overall, the treatment groups were similar with respect to sex, race, age, and baseline pain intensity. ‘Pain intensity was graded on a 4-point scale where 0 = none, 1 = slight, 2 = moderate,
point from the first pain assessment at 0.5 hour through the last assessment at 24 hours, the pain relief scores for rofecoxib were significantly greater than for diclofenac (P < 0.001) and placebo (P < 0.001). Based on patient global assessments at 8 hours, a greater percentage of rofecoxib-treated patients were responders (good, very good, or excellent) compared with diclofenac sodium-treated patients (100 [84.0%] vs 34 [29.1%]; P < 0.001) and placebo patients (100 [84.0%] vs 14 [23.0%]; P < 0.001) (Figure 2). The percentages of rofecoxib-treated patients with good, very good, or excellent responses at 8 hours were 18.5%, 42.0%, and 23.5%, respectively. The mean patient global assessment score at 8 hours was greater for patients taking rofecoxib than for patients taking diclofenac (2.7 vs 0.9; P < 0.001) and placebo (2.7 vs 0.7; P < 0.001). The
and 3 = severe.
patient global assessment at 24 hours showed a greater percentage of responders among patients treated with a single dose of rofecoxib than among patients treated with 3 doses of diclofenac sodium (101 [84.2%] vs 28 [23.9%]; P < 0.001) or placebo (101 [84.2%] vs 14 [23.0%]; P < 0.001) (Figure 3). The percentages of rofecoxib-treated patients with good, very good, or excellent ratings at 24 hours were 20.0%, 31.7%, and 32.5%, respectively. These results corresponded to a higher 24-hour mean patient global assessment score for rofecoxib patients compared with diclofenac patients (2.7 vs 0.9; P < 0.001) and placebo patients (2.7 vs 0.7; P < 0.001). Onset of Analgesic Effect The median time to onset of analgesic
effect was more rapid for rofecoxib (31 minutes) than for diclofenac sodium (>4
CLINICAL THERAPEUTICS”
Table II. Analgesic effkacy of rofecoxib, diclofenac sodium, and placebo in patients with moderate to severe postoperative dental pain.* Rofecoxib (50 mg) (n = 121)
Diclofenac Sodium (50 mg 98h) (n = 121)
Placebo (n = 63)
20.5* (18.9, 22.1) 64.1# (58.8,69.5)
8.2 (6.6,9.8) 25.1 (19.7, 30.5)
5.9 (3.7, 8.1) 19.2 (11.9,26.6)
Patient global assessment at 8 h (o-4 scale)5
2.7t (2.5, 2.9)
0.9 (0.7, 1.1)
0.7 (0.4. 1.0)
Patient global assessment at 24 h (O-4 scale)$
2.7$ (2.5,2.9)
0.9 (0.7, 1.1)
0.7 (0.4, 1.0)
0:31* (0:28, 0:45)
(>4:00, >4:00)
(>4:00, A:OO)
3.2$ (3.0, 3.4)
1.5 (1.3, 1.8)
1.1 (0.8, 1.4)
>24:00+ (>24:00, >24:00)
1:37 (1:35, 2:09)
1:37 (1:35,2:07)
Overall analgesic effect+ TOPARS (O-32 scale) TOPAR (0-% scale)
Onset of analgesic effect Median time (hmin) to confirmed perceptible
pain relief
Peak analgesic effect Peak pain relief (O-4 scale)1 Duration of analgesic effect Median time (h:min) to use of rescue analgesic medication
>4:00”
>4:00”
TOPARB = total pain relief over 8 hours; TOPAR = total pain relief over 24 hours. *Values are reported as least-square means (95% CI), unless otherwise indicated. tPain relief was graded on a 5-point scale where 0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete. Total pain relief scores represent the sum of pain relief scores over 8 hours (TOPARS) or 24 hours (TOPAR24). *P < 0.001 versus both diclofenac sodium and placebo. $0 = poor; 1 = fair; 2 = good; 3 = very good; 4 = excellent. “Less than 50% of the patients achieved confirmed perceptible pain relief within 4 hours. PMaximum pain relief achieved during the hrst 8 hours (0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete).
hours for most patients; P < 0.001). For both diclofenac and placebo, the onset of analgesia was >4 hours, as 40% of the patients experienced perceptible and meaningful pain relief within a 4-hour period. Peak Analgesic Effect The maximum analgesic effect of rofecoxib within 8 hours of the initial study medication dose, as determined by peak
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pain relief, was greater than that of diclofenac sodium (3.2 vs 1.5; P c 0.001) and placebo (3.2 vs 1.1; P < 0.001). Duration of Analgesic Effect The median time to use of rescue analgesia was significantly longer for patients taking rofecoxib compared with those taking diclofenac sodium (>24 hours vs 1 hour and 37 minutes; P < 0.001) or placebo
D.J. CHANG ET AL
G Rofecoxib 50 mg --A Diclofenac 50 mg q8h -El- Placebo
of 0
, 2
I
I
I
I
I
I
I
I
I
I
I
4
6
8
10
12
14
16
18
20
22
24
Hours After Initial Dose
Figure 1. Mean (GE) pain relief scores in patients experiencing moderate to severe postoperative dental pain over the 24 hours after initial study drug dosing. Patients who used rescue medication are included; the last reported value was carried forward. *P < 0.001 versus diclofenac and placebo. (>24 hours vs 1 hour and 37 minutes; P < 0.001). At 8 hours, significantly fewer rofecoxib-treated patients required rescue medication (24 [ 19.8%]) than did diclofenactreated patients (8 1 [66.9%]) or those taking placebo (48 [76.2%]) (P < 0.001). For the entire 24-hour assessment period, signiticantly fewer patients taking rofecoxib needed rescue medication than did patients taking diclofenac (35 [28.9%] vs 92 [76.0%]; P < 0.001) or those taking placebo (35 [28.9%] vs 50 [79.4%]) (P < 0.001). Other Measures
of Analgesic
Effect
Because diclofenac sodium did not provide as much pain relief as would be ex-
pected for a drug effective in the treatment of pain, osteoarthritis, and rheumatoid arthritis, we performed additional exploratory analyses to investigate the overall analgesic effect of the study medications. Patients were permitted to take rescue medication at any time after the initial dose of study medication. Consequently, the slower onset of action for diclofenac sodium may have impacted the diclofenac TOPAR results more than the rofecoxib TOPAR results, as the prespecified primary method of analysis carried forward pain scores when patients took rescue medication. Results for TOPAR and TOPAR were analyzed using efficacy data from all the pre497
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0
Poor Fair Good B Very good H Excellent
n n
Placebo (n = 61)
Diclofenac 50 mg q8h (n= 117)
Rofecoxib 50 mg (n=119)
Responders
Nonresponders
Figure 2. Patient global assessment at 8 hours after administration of initial dose of study medication. Patients who rated their response as good, very good, or excellent were considered responders; those who rated their response as poor or fair were considered nonresponders. *P< 0.001 versus diclofenac and placebo.
specified times, irrespective of rescue analgesia use (pain assessments at the time of rescue medication use were not carried forward). Using this secondary approach, TOPAR for a single dose of diclofenac sodium 50 mg was greater than for placebo (18.4 vs 15.6; P < 0.010); TOPAR for a single dose of rofecoxib 50 mg was greater than a single dose of diclofenac sodium 50 mg (22.2 vs 18.4; P < 0.001) and placebo (22.2 vs 15.6; P < 0.001). For the entire 24 hours, TOPAR for 3 doses of diclofenac sodium 50 mg was greater than for placebo (65.2 vs 57.0; P < 0.010); TOPAR for a single dose of rofecoxib 50 mg was greater than for 3 doses of diclofenac sodium 50 mg (72.4 vs 65.2; P < 0.001) or placebo (72.4 vs 57.0; P < 0.001).
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Safety ProjTle
One serious adverse event was reported in a patient randomized to placebo who developed an asthma flare and withdrew from the study. The investigator study determined the adverse event to be possibly drug related. No other patients were withdrawn from the study due to an adverse experience. Adverse experiences were reported in 53 (43.8%), 71 (58.7%), and 31 (49.2%) of the patients taking rofecoxib, diclofenac, and placebo, respectively. More events occurred in the diclofenac group compared with the rofecoxib group (P < 0.05). Although more events were detected in the diclofenac group than in the placebo group, the dif-
D.J. CHANG ET AL.
0 Poor n Fair n Good 0 Very good q Excellent Placebo (n=61)
Diclofenac 50 mg q8h (n = 117)
23.0%
77.0%
7&j%
Rofecoxib 50 mg (n = 120)
Nonresponders
Responders
Figure 3. Patient global assessment at 24 hours after administration of initial dose of study medication. Patients who rated their response as good, very good, or excellent were considered responders; those who rated their response as poor or fair were considered nonresponders. *P< 0.001 versus diclofenac and placebo.
ference was not statistically significant. Drug-related side effects were reported in 13 (10.7%), 27 (22.3%), and 11 (17.5%) of the patients taking rofecoxib, diclofenac, and placebo, respectively. There were more events among the diclofenactreated patients than rofecoxib-treated patients (P < 0.05). The difference between diclofenac and placebo, although numerically higher for diclofenac, did not achieve statistical significance. The most common adverse events (occurring in 25% of patients in any treatment group) were headache, nausea, dizziness, postextraction alveolitis, vomiting, and pharyngitis (Table III). There were no significant between-group differences in the incidence of any of these adverse experiences.
DISCUSSION The postoperative dental-impaction pain model is a well-validated and sensitive model for assessing the efficacy of analgesic drugs in humans.‘* This dental pain study demonstrated that a single dose of rofecoxib 50 mg was superior in overall analgesic efficacy compared with a single dose of enteric-coated diclofenac sodium 50 mg over an 8-hour period as well as 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours) over a 24hour period. The overall efficacy was determined by TOPAR, which is the sum of time-weighted pain relief scores over the specified time intervals, as well as by patient global assessments at 8 and 24 hours. Other standard measures of analgesic
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Table III. Number (%) of patients with specific clinical adverse experience 25% of any treatment group.* Rofecoxib (50 mg) (n = 121) Headache Nausea Dizziness Postextraction alveolitis Vomiting Pharyngitis *There were no significant
21 (17.4) 14 (11.6) 5 (4.1) 7 (5.8) 2 (1.7) 1 (0.8) differences
32 21 9 9 6 6
(26.4) (17.4) (7.4) (7.4) (5.0) (5.0)
in
Placebo (n = 63) 18 (28.6) 10 (15.9) 5 (7.9) 3 (4.8) 7 (11.1) 2 (3.2)
among the treatment groups.
efficacy---onset of effect, peak effect, and duration of effect-also demonstrated a significantly greater effect for rofecoxib compared with enteric-coated diclofenac sodium. Similarly, other single-dose dental pain studies have suggested that enteric-coated diclofenac sodium may not be as effective in treating acute pain as other NSAIDs including naproxen 500 mg, l4 flurbiprofen 100 mg,21 and aspirin 650 mg.12 Consistent with prior acute dental pain studies2,5,6 in which the onset of analgesic effect for rofecoxib occurred within 45 minutes, the current study demonstrated that patients treated with rofecoxib achieved confirmed perceptible pain relief at 31 minutes. The onset of effect for enteric-coated diclofenac sodium was significantly slower than for rofecoxib, which supports prior acute dental pain studies showing the slower onset of entericcoated diclofenac sodium 50 mg compared with flurbiprofen 100 mg2i and enteric-coated diclofenac sodium 75 mg compared with naproxen 500 mg.i4 To address the issue of a slower analgesic onset of enteric-coated diclofenac sodium
500
Diclofenac Sodium (50 m8 q8h) (n = 121)
occurring
compared with rofecoxib, a post-hoc exploratory analysis was performed using pain scores from all the times, including those provided after rescue medication was taken. Applying this secondary approach to the data analysis, TOPARS and TOPAR results were significantly greater for enteric-coated diclofenac sodium than for placebo. Both TOPARS and TOPAR were still significantly greater for rofecoxib than for entericcoated diclofenac sodium and placebo. The differences among the groups favoring rofecoxib persisted even though the percentage of patients requiring rescue medication was more than 3 times greater for enteric-coated diclofenac sodium than for rofecoxib over 8 hours (66.9% vs 19.8%; P c 0.001) and more than 2.5 times greater for enteric-coated diclofenac sodium than for rofecoxib over 24 hours (76.0% vs 28.9%; P < 0.001). This analysis also demonstrated that enteric-coated diclofenac sodium did, in fact, have a significantly greater analgesic effect than placebo, which is in agreement with prior acute dental pain studies l&l3 of orally administered, enteric-coated diclofenac sodium 50 mg.
D.J. CHANG ET AL.
The enteric coating of diclofenac sodium may have contributed to the delayed onset of analgesic effect. Other formulations of diclofenac, including intravenous diclofenac sodium,22 oral dispersible diclofenac sodium,23,24 and oral diclofenac potassium,25326 have shown a more rapid onset of action than oral enteric-coated diclofenac sodium for postoperative dental pain. Thus any extrapolation to comparisons with these agents cannot be made. Safety assessment showed that rofecoxib and enteric-coated diclofenac sodium were generally well tolerated. Only 1 serious adverse event was reported in a patient randomized to placebo. The incidences of any adverse events and drugrelated adverse events were significantly higher for enteric-coated diclofenac sodium than for rofecoxib; no statistical difference was detected between rofecoxib and placebo, although the rates were numerically higher for placebo. The higher incidence of side effects associated with enteric-coated diclofenac sodium may have been due to the higher utilization of opioid-containing rescue medication among enteric-coated diclofenac sodium-treated patients. This theory, however, is not completely supported by the examination of the placebo group, which had adverse event rates numerically lower than the enteric-coated diclofenac sodium group despite greater use of rescue opioid analgesia.
CONCLUSIONS In this study, a single dose of rofecoxib 50 mg, the recommended dose for the treatment of acute pain, provided greater overall analgesic efficacy over 8 hours (as determined by TOPAR and patient global
assessment at 8 hours), more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of action than a single dose of enteric-coated diclofenac sodium 50 mg in patients with moderate to severe pain associated with impacted third molar dental surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours (as determined by TOPAR and patient global assessment at 24 hours). When efficacy measurements recorded after patients took rescue medication were included in the analysis, a single 50-mg dose of rofecoxib still demonstrated greater overall analgesic efficacy than did a single dose of entericcoated diclofenac sodium 50 mg on TOPAR and 3 doses of enteric-coated diclofenac sodium 50 mg on TOPAR24; both rofecoxib and enteric-coated diclofenac sodium had greater overall analgesic efficacy than placebo on TOPARS and TOPAR24. Rofecoxib-treated patients experienced a lower incidence of any adverse events and drug-related adverse events than did enteric-coated diclofenac sodium-treated patients.
ACKNOWLEDGMENTS The study was funded by a grant from Merck & Co, Inc, West Point, Pennsylvania. The authors thank Drs. Janet Rush, William Keane, and John Yates for their review of the manuscript and helpful comments. The authors also would like to acknowledge the active participation of the following investigators and study staff: Yuki Morris (Project Manager), Dr. Julius Hyatt (Principal Investigator [PI], SCIREX CRC, Baltimore, Maryland), Dr. Donald
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Bandy (PI, SCIREX CRC, San Marcos, Texas), Dr. Roger Badwal (PI, SCIREX CRC, Windsor, Connecticut). Dr. Desjardins served as PI for the SCIREX CRC, Austin, Texas. The following staff served as lead clinical coordinators: Diego Ceniceros, Suzan Schwing, Janine Ritchie, and Joan LeBlanc.
REFERENCES 1. Morrison SW, Christensen S, Yuan W, et al. Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: A randomized, controlled trial. Clin Thel: 1999,21:943-953.
2. Morrison
SW, Fricke J, Brown J, et al. The optimal analgesic dose of rofecoxib: Overview of six randomized controlled trials. JAm Dent Assoc. 2000;131:17291737.
3. Reicin A, Brown J, Jove M, et al. Efficacy of single-dose and multidose rofecoxib in the treatment of post-orthopedic surgery pain. Am J Orthop. 2001;30:4048.
7. Jones R. Nonsteroidal anti-inflammatory drug prescribing: Past, present, and future. Am JMed. 2001;110:4S-7s. 8. Patient Days of Therapy 3QOl and Prescriptions 2QO1. London: International Medical Statistics; 2001. (diclofenac sodium) 9. Voltaren@ Cataflam@ (diclofenac potassium). Physicians’ Desk Reference@. 56th Montvale, NJ: Medical Economics 2002:2315-2319.
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10. Bakshi R, Jacobs LD, Lehnert S, et al. A double-blind, placebo-controlled trial comparing the analgesic efficacy of two formulations of diclofenac in postoperative dental pain. Curr Ther Res. 1992;52: 435442. 11. Adair SF, Mehlisch DR, Brandes S, et al. Diclofenac sodium (Voltaten) shows analgesic efficacy in dental pain model. Clin Phannacol Thel: 1988;28:915. Abstract. 12. Waiter SL, Cooper SA, Finizio TA, et al. Analgesic efficacy of 50 and 100 mg diclofenac sodium compared to aspirin 650 mg in dental pain. Clin Pharmacol Thel: 1987;41:230. Abstract.
4. Morrison SW, Daniels SE, Kotey P, et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: A randomized controlled trial. Obstet Gynecol. 1999;94:504-508.
5. Malmstrom
K, Daniels S, Kotey P, et al. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: A randomized, placebo- and active-comparator-controlled clinical trial. Clin Thel: 1999;21:1653-1663.
13. Mehlisch DR, Bocanegra TS, Callison D, Wallemark C. Analgesic activity of a fixed combination of diclofenac plus misoprostol in dental pain. Paper presented at: The American Pain Society 15th Annual Meeting; November 14-17, 1996, Washington, DC.
6. Chang DJ, Fricke JR, Bird SR, et al.
14. Mehlisch D, Kiersch T, Brown P, et al. Pain relief following dental impaction surgery using naproxen, diclofenac sodium (enteric-coated), or placebo. J Clin Pharmacol. 1991;31:856. Abstract.
Rofecoxib versus codeinelacetaminophen in postoperative dental pain: A doubleblind, randomized, placebo- and active comparator-controlled clinical trial. Clin Thel: 2001;23:1446-1455.
15. Ingemanson CA, Carrington B, Sikstrom B. Diclofenac in the treatment of primary dysmenorrhea. Curr Ther Res. 1981;30: 632-639.
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16. Riihiluoma P, Wuolijoki E, Pulkkinen MO. Treatment of primary dysmenorrhea with diclofenac sodium. Eur J Obsret Gynecol Reprod Biol. 1981;12:189-194.
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Seymour RA, Moore U, Hawkesford J, et al. An investigation into the efficacy of intravenous diclofenac in post-operative dental pain. Eur J Clin Pharmacol. 2000; 56:447452.
17. Massiou H, Serrurier D, Lasserre 0, Bousser MG. Effectiveness of oral diclofenac in the acute treatment of common migraine attacks: A double-blind study versus placebo. Cephalalgia. 199 1; 11:59-63.
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18. Forbes JA. Oral surgery. In: Max MB, Portenoy RK, Laska EM, eds. Advances in Pain Research sign of Analgesic
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Ahlstrom U, Bakshi R, Nilsson P, Wahlander L. The analgesic efficacy of diclofenac dispersible and ibuprofen in postoperative pain after dental extraction. Eur .I Clin Pharmacol.
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Mehlisch DR, Brown l? Single-dose therapy with diclofenac potassium, aspirin, or placebo following dental impaction surgery. Today’s Ther Trends. 1994;12: 1531.
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Nelson S, Brahim analgesic efficacy sium, aspirin, and tive dental pain.
20. Desjardins PJ, Black PM, Balm TK, et al. Onset of analgesia: Further validation of a new stopwatch methodology. Clin Pharmacol The,: 1996;59: 130. Abstract. 21. Frame JW, Rout PG. A comparison of the analgesic efficacy of flurbiprofen, diclofenac, dihydrocodeine/paracetamol and placebo following oral surgery. Br J Clin
Bakshi R, Frenkel G, Dietlein G, et al. A placebo-controlled comparative evaluation of diclofenac dispersible versus ibuprofen in postoperative pain after third molar surgery. J Clin Pharmacol. 1994;34:225-
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Address correspondence to: David J. Chang, MD, Merck & Co, Inc, HM 202, PO Box 4, West Point,
PA 19486-0004.
503
Comparison of the Analgesic Efficacy of Rofecoxib and Enteric-Coated Diclofenac Sodium in the Treatment of Postoperative Dental Pain: A Randomized, Placebo-Controlled Clinical Trial David J. Chang, MD,’ Paul J. Desjardins, DMD, PhD,2 Erluo Chen, MPH,, Adam B. Polis, MA,’ Mary McAvoy, MMS,’ Sandra H. Mockoviuk, BS,l and Gregory I? Geba, MD’ ‘Merck & Co, Inc, West Point, Pennsylvania, and 2SCIREX Corporation, Austin, Texas, and Department of Oral Pathology, Biology and Diagnostic Sciences, University of Medicine and Dentistry, New Jersey Dental School, Newark, New Jersey
ABSTRACT Background: Rofecoxib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. Objective: The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. Methods: In this double-blind, placebo- and active comparator-controlled, parallelgroup study, patients experiencing moderate to severe pain after the surgical extraction of 22 third molars were randomized to receive a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPARS) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. Results: A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% exAccepted
for publication
February 28, 2002.
Printed in the USA. Reproduction
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perienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with entericcoated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and ~4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (~24 hours vs 1 hour and 37 minutes). Entericcoated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, al-
though the rofecoxib group had a significantly lower incidence of clinical and drugrelated adverse events than the entericcoated diclofenac sodium group. Conclusions: A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours. Key words: rofecoxib, diclofenac, cyclooxygenase-2 inhibitor, nonsteroidal antiinflammatory drug, postoperative dental pain, oral surgery, analgesic. (C/in Thel: 2002;24:490-503)
INTRODUCTION Rofecoxib is a selective cyclooxygenase2 inhibitor with demonstrated efficacy in acute analgesic models of postoperative dental pain,“2 postorthopedic surgery pain3 and primary dysmenorrhea.4 In the postoperative dental impaction pain model, rofecoxib 50 mg is similar in overall analgesic efficacy to maximum single analgesic doses of ibuprofen and naproxen sodium,“2 superior to celecoxib 200 mg,5 and superior to codeine 60 mg with acetaminophen 600 mg.6 However, based on a MEDLINE search (1966 through February 2002) using the terms rofecoxib and diclofenac, no studies of acute pain management have compared the analgesic efficacy of rofecoxib with diclofenac, the most commonly prescribed nonsteroidal anti-inflammatory drug (NSAID) world-
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wide.7*8 Although indicated for the treatment of the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis in the United States,9 oral enteric-coated diclofenac sodium is also effective in a variety of acute pain settings such as postoperative oral surgery pain, lo-l4 dysmenorrhea,15*16 and acute migraine.i7 The objectives of this investigation were to compare the analgesic effects of a single dose of rofecoxib 50 mg and a single dose of enteric-coated diclofenac sodium 50 mg over an &hour period, and to compare a single dose of rofecoxib 50 mg and 3 doses of enteric-coated diclofenac sodium 50 mg over a 24-hour period, using a standard, validated postoperative dental pain model. l8 Immediate-release diclofenac potassium, while available in the United States, is not widely available or prescribed in other countries8; therefore, it was not selected as the comparator agent in this study.
PATIENTS
AND METHODS
Patients Patients were eligible to participate in the study if they were healthy males or females, 216 years of age, and scheduled to undergo surgical removal of 22 third molars, at least 1 of which was partially embedded in the mandibular bone. Standard intraoperative anesthesia was allowed, including lidocaine, midazolam, fentanyl, and nitrous oxide. Only participants experiencing moderate to severe pain on a categorical verbal pain scale were randomized. Reasons for exclusion included allergic reactions or intolerance to aspirin, NSAIDs, acetaminophen, or hydrocodone bitartrate; concomitant use of tricyclic an-
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tidepressants, 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 that might confound the results of the study or pose additional risk to the patients. All women were required to have negative results on urine pregnancy testing. Before enrollment in the study, all patients provided written informed consent on a form approved by an institutional review board. Study Design This randomized, double-blind, placeboand active comparator-controlled, parallelgroup study was conducted at 4 centers. All patients were enrolled over a 4week period. Following third molar extraction surgery, patients who reported moderate or severe pain were eligible for randomization to a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given orally every 8 hours), or placebo in a 2:2: 1 ratio. The rofecoxib dose used is the indicated dose for analgesia.19 Prior studies have shown the effectiveness of diclofenac sodium 50 mg in the acute dental pain model.10-13 The dosing frequency of diclofenac sodium 50 mg every 8 hours was consistent with the recommended prescribing information, which is 50 mg twice daily or 3 times daily (TID) for osteoarthritis and 50 mg TID or 4 times daily for rheumatoid arthritis.9 When used for analgesia, the recommended starting dose for the immediate-release formulation of diclofenac is 50 mg TID.9 Randomization was stratified based on the baseline pain intensity of moderate or severe on a categorical verbal pain scale using a
D.J. CHANG ET AL.
computer-generated allocation schedule. The study medications were administered to patients in a double-dummy fashion. To maintain blinding, rofecoxib or its matching placebo was administered at baseline to all patients; diclofenac sodium or its matching placebo was given at baseline, 8 hours, and 16 hours to all patients. After study medication was taken, patients rated pain intensity, pain relief, and global assessments at 17 prespecified times over a 24-hour period. Patients were required to remain at the study site for 24 hours after the initial dosing of the study medication. Patients who experienced inadequate pain relief were allowed to take rescue analgesic medication (hydrocodone/ acetaminophen 5/500 mg) at any time.
Efficacy Assessments Patients recorded their pain intensity and pain relief at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, and 24 hours after administration of the initial dose of study medication. Standard and established pain rating scales for postoperative dental pain were used.‘* Pain intensity was recorded on a 4-point categorical verbal scale (0 = none, 1 = slight, 2 = moderate, and 3 = severe); pain relief was recorded on a 5-point categorical verbal scale (0 = none, 1 = a little, 2 = some, 3 = a lot, and 4 = complete). Patients provided global assessments at 8 hours and 24 hours (0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent), with nonresponders including patients with a poor or fair rating and responders including patients with good, very good, or excellent rating. The overall analgesic efficacy was determined by total pain relief over 8 hours (TOPARS; range 0 to 32) and 24 hours (TOPAR24; range 0 to 96) and patient
global assessments at 8 hours and 24 hours. TOPARS and TOPAR were derived by summing time-weighted pain relief scores over g-hour and 24-hour periods, respectively. Other end points in the study included onset of analgesic effect, peak analgesic effect, duration of analgesic effect, and percentage of patients requiring rescue medication within 8 and 24 hours. Onset of analgesic effect was determined using 2 stopwatches, which were started at the time of the administration of the initial dose of study drug. 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).2o If perceptible pain relief was obtained without associated meaningful pain relief, a censored value of 4 hours was used. Peak analgesic effect was the maximum pain relief achieved during the first 8 hours. The duration of analgesic effect was determined by calculating the median time to rescue medication use. Adverse events were determined based on spontaneous reporting by patients. If patients required rescue analgesia, they recorded their pain intensity, pain relief, and global assessments just prior to taking the first rescue medication.
Safety Assessments The safety of the study medications was determined by limited physical examination, vital signs, and spontaneous reporting of any adverse experiences. After the occurrence of an adverse experience but prior
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to unblinding, investigators determined the adverse experience was related to study drug. Events that were considered the investigator to be possibly, probably, definitely drug-related were recorded drug-related adverse experiences.
if the by or as
Statistical Analysis The primary objective of the study was to compare TOPARS of rofecoxib and enteric-coated diclofenac sodium. Based on estimates from prior rofecoxib dental pain studies’,2,5,6 and enteric-coated diclofenac sodium dental pain studies,iO,’ 1 the sample size of 120 patients per group was calculated to provide 92% power to declare that rofecoxib was superior (P < 0.05) to diclofenac. Efficacy analyses were based on a modified intent-to-treat approach. This approach included all patients treated with a baseline assessment and at least 1 measurement after the initial medication dosing. For pain intensity, pain relief, and patient global assessment, missing values were estimated by carrying forward the last available observation. If rescue medication was taken, the recorded assessments (pain intensity, pain relief, and patient global assessment) at the time of first rescue analgesia use were carried forward. Pairwise treatment comparisons for TOPAR8, TOPAR24, patient global assessment scores at 8 and 24 hours, and peak pain relief were analyzed using an analysis of variance model with factors for treatment group, baseline pain intensity, and study center. A logistic regression model with factors for treatment group, baseline pain intensity, and study center was used in the analysis of the percentage of patients taking rescue medication and patient global assessment in terms of responders (good, very good, or excel494
lent) versus nonresponders (fair or poor). Analysis of time to confirmed perceptible pain relief and time to first rescue medication were performed using Kaplan-Meier time-to-event estimate with corresponding Wilcoxon statistics. All randomized and treated patients were included in the assessment of safety. The Fisher 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 < 0.05 (2-tailed).
RESULTS A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline characteristics among the treatment groups were generally similar with respect to sex, race, age, and baseline pain intensity (Table I). Overall, 61.3% (187 of 305) had moderate baseline pain and 38.7% (118 of 305) had severe baseline pain.
EJGcacy Overall Analgesic Effect The overall analgesic effect over 8 hours, as measured by the primary end point TOPAR8, was significantly greater for a single dose of rofecoxib 50 mg than for a single dose of diclofenac sodium 50 mg (20.5 vs 8.2; P < 0.001) and placebo (20.5 vs 5.9; P < 0.001) (Table II). For the 24hour assessment TOPAR24, a single dose of rofecoxib 50 mg provided significantly greater pain relief than 3 doses of diclofenac sodium 50 mg (64.1 vs 25.1; P c 0.001) or placebo (64.1 vs 19.2; PC 0.001). The pain relief scores over a 24-hour period are shown in Figure 1. At every time
D.J. CHANG ET AL.
Table I. Baseline characteristics,
by treatment Rofecoxib
group.* Diclofenac
Sodium
(50 mg) (n = 121)
(50 mg q8b) (n = 121)
Placebo (n = 63)
Sex, no. (%) Male Female
62 (51.2) 59 (48.8)
48 (39.7) 73 (60.3)
33 (52.4) 30 (47.6)
Race, no. (%) White Other Black Asian Multiracial
65 34 18 2 2
77 23 15 4 2
45 (7 1.4) 7 (11.1) 7 (11.1) l(l.6) 3 (4.8)
Age, y (mean + SD)
24.2 f 5.1
22.8 + 5.0
22.8 + 4.4
Baseline pain intensity,’ no. (%) Moderate Severe
73 (60.3) 48 (39.7)
76 (62.8) 45 (37.2)
38 (60.3) 25 (39.7)
(53.7) (28.1) (14.9) (1.7) (1.7)
(63.6) (19.0) (12.4) (3.3) (1.7)
*Overall, the treatment groups were similar with respect to sex, race, age, and baseline pain intensity. ‘Pain intensity was graded on a 4-point scale where 0 = none, 1 = slight, 2 = moderate,
point from the first pain assessment at 0.5 hour through the last assessment at 24 hours, the pain relief scores for rofecoxib were significantly greater than for diclofenac (P < 0.001) and placebo (P < 0.001). Based on patient global assessments at 8 hours, a greater percentage of rofecoxib-treated patients were responders (good, very good, or excellent) compared with diclofenac sodium-treated patients (100 [84.0%] vs 34 [29.1%]; P < 0.001) and placebo patients (100 [84.0%] vs 14 [23.0%]; P < 0.001) (Figure 2). The percentages of rofecoxib-treated patients with good, very good, or excellent responses at 8 hours were 18.5%, 42.0%, and 23.5%, respectively. The mean patient global assessment score at 8 hours was greater for patients taking rofecoxib than for patients taking diclofenac (2.7 vs 0.9; P < 0.001) and placebo (2.7 vs 0.7; P < 0.001). The
and 3 = severe.
patient global assessment at 24 hours showed a greater percentage of responders among patients treated with a single dose of rofecoxib than among patients treated with 3 doses of diclofenac sodium (101 [84.2%] vs 28 [23.9%]; P < 0.001) or placebo (101 [84.2%] vs 14 [23.0%]; P < 0.001) (Figure 3). The percentages of rofecoxib-treated patients with good, very good, or excellent ratings at 24 hours were 20.0%, 31.7%, and 32.5%, respectively. These results corresponded to a higher 24-hour mean patient global assessment score for rofecoxib patients compared with diclofenac patients (2.7 vs 0.9; P < 0.001) and placebo patients (2.7 vs 0.7; P < 0.001). Onset of Analgesic Effect The median time to onset of analgesic
effect was more rapid for rofecoxib (31 minutes) than for diclofenac sodium (>4
CLINICAL THERAPEUTICS”
Table II. Analgesic effkacy of rofecoxib, diclofenac sodium, and placebo in patients with moderate to severe postoperative dental pain.* Rofecoxib (50 mg) (n = 121)
Diclofenac Sodium (50 mg 98h) (n = 121)
Placebo (n = 63)
20.5* (18.9, 22.1) 64.1# (58.8,69.5)
8.2 (6.6,9.8) 25.1 (19.7, 30.5)
5.9 (3.7, 8.1) 19.2 (11.9,26.6)
Patient global assessment at 8 h (o-4 scale)5
2.7t (2.5, 2.9)
0.9 (0.7, 1.1)
0.7 (0.4. 1.0)
Patient global assessment at 24 h (O-4 scale)$
2.7$ (2.5,2.9)
0.9 (0.7, 1.1)
0.7 (0.4, 1.0)
0:31* (0:28, 0:45)
(>4:00, >4:00)
(>4:00, A:OO)
3.2$ (3.0, 3.4)
1.5 (1.3, 1.8)
1.1 (0.8, 1.4)
>24:00+ (>24:00, >24:00)
1:37 (1:35, 2:09)
1:37 (1:35,2:07)
Overall analgesic effect+ TOPARS (O-32 scale) TOPAR (0-% scale)
Onset of analgesic effect Median time (hmin) to confirmed perceptible
pain relief
Peak analgesic effect Peak pain relief (O-4 scale)1 Duration of analgesic effect Median time (h:min) to use of rescue analgesic medication
>4:00”
>4:00”
TOPARB = total pain relief over 8 hours; TOPAR = total pain relief over 24 hours. *Values are reported as least-square means (95% CI), unless otherwise indicated. tPain relief was graded on a 5-point scale where 0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete. Total pain relief scores represent the sum of pain relief scores over 8 hours (TOPARS) or 24 hours (TOPAR24). *P < 0.001 versus both diclofenac sodium and placebo. $0 = poor; 1 = fair; 2 = good; 3 = very good; 4 = excellent. “Less than 50% of the patients achieved confirmed perceptible pain relief within 4 hours. PMaximum pain relief achieved during the hrst 8 hours (0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete).
hours for most patients; P < 0.001). For both diclofenac and placebo, the onset of analgesia was >4 hours, as 40% of the patients experienced perceptible and meaningful pain relief within a 4-hour period. Peak Analgesic Effect The maximum analgesic effect of rofecoxib within 8 hours of the initial study medication dose, as determined by peak
496
pain relief, was greater than that of diclofenac sodium (3.2 vs 1.5; P c 0.001) and placebo (3.2 vs 1.1; P < 0.001). Duration of Analgesic Effect The median time to use of rescue analgesia was significantly longer for patients taking rofecoxib compared with those taking diclofenac sodium (>24 hours vs 1 hour and 37 minutes; P < 0.001) or placebo
D.J. CHANG ET AL
G Rofecoxib 50 mg --A Diclofenac 50 mg q8h -El- Placebo
of 0
, 2
I
I
I
I
I
I
I
I
I
I
I
4
6
8
10
12
14
16
18
20
22
24
Hours After Initial Dose
Figure 1. Mean (GE) pain relief scores in patients experiencing moderate to severe postoperative dental pain over the 24 hours after initial study drug dosing. Patients who used rescue medication are included; the last reported value was carried forward. *P < 0.001 versus diclofenac and placebo. (>24 hours vs 1 hour and 37 minutes; P < 0.001). At 8 hours, significantly fewer rofecoxib-treated patients required rescue medication (24 [ 19.8%]) than did diclofenactreated patients (8 1 [66.9%]) or those taking placebo (48 [76.2%]) (P < 0.001). For the entire 24-hour assessment period, signiticantly fewer patients taking rofecoxib needed rescue medication than did patients taking diclofenac (35 [28.9%] vs 92 [76.0%]; P < 0.001) or those taking placebo (35 [28.9%] vs 50 [79.4%]) (P < 0.001). Other Measures
of Analgesic
Effect
Because diclofenac sodium did not provide as much pain relief as would be ex-
pected for a drug effective in the treatment of pain, osteoarthritis, and rheumatoid arthritis, we performed additional exploratory analyses to investigate the overall analgesic effect of the study medications. Patients were permitted to take rescue medication at any time after the initial dose of study medication. Consequently, the slower onset of action for diclofenac sodium may have impacted the diclofenac TOPAR results more than the rofecoxib TOPAR results, as the prespecified primary method of analysis carried forward pain scores when patients took rescue medication. Results for TOPAR and TOPAR were analyzed using efficacy data from all the pre497
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0
Poor Fair Good B Very good H Excellent
n n
Placebo (n = 61)
Diclofenac 50 mg q8h (n= 117)
Rofecoxib 50 mg (n=119)
Responders
Nonresponders
Figure 2. Patient global assessment at 8 hours after administration of initial dose of study medication. Patients who rated their response as good, very good, or excellent were considered responders; those who rated their response as poor or fair were considered nonresponders. *P< 0.001 versus diclofenac and placebo.
specified times, irrespective of rescue analgesia use (pain assessments at the time of rescue medication use were not carried forward). Using this secondary approach, TOPAR for a single dose of diclofenac sodium 50 mg was greater than for placebo (18.4 vs 15.6; P < 0.010); TOPAR for a single dose of rofecoxib 50 mg was greater than a single dose of diclofenac sodium 50 mg (22.2 vs 18.4; P < 0.001) and placebo (22.2 vs 15.6; P < 0.001). For the entire 24 hours, TOPAR for 3 doses of diclofenac sodium 50 mg was greater than for placebo (65.2 vs 57.0; P < 0.010); TOPAR for a single dose of rofecoxib 50 mg was greater than for 3 doses of diclofenac sodium 50 mg (72.4 vs 65.2; P < 0.001) or placebo (72.4 vs 57.0; P < 0.001).
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Safety ProjTle
One serious adverse event was reported in a patient randomized to placebo who developed an asthma flare and withdrew from the study. The investigator study determined the adverse event to be possibly drug related. No other patients were withdrawn from the study due to an adverse experience. Adverse experiences were reported in 53 (43.8%), 71 (58.7%), and 31 (49.2%) of the patients taking rofecoxib, diclofenac, and placebo, respectively. More events occurred in the diclofenac group compared with the rofecoxib group (P < 0.05). Although more events were detected in the diclofenac group than in the placebo group, the dif-
D.J. CHANG ET AL.
0 Poor n Fair n Good 0 Very good q Excellent Placebo (n=61)
Diclofenac 50 mg q8h (n = 117)
23.0%
77.0%
7&j%
Rofecoxib 50 mg (n = 120)
Nonresponders
Responders
Figure 3. Patient global assessment at 24 hours after administration of initial dose of study medication. Patients who rated their response as good, very good, or excellent were considered responders; those who rated their response as poor or fair were considered nonresponders. *P< 0.001 versus diclofenac and placebo.
ference was not statistically significant. Drug-related side effects were reported in 13 (10.7%), 27 (22.3%), and 11 (17.5%) of the patients taking rofecoxib, diclofenac, and placebo, respectively. There were more events among the diclofenactreated patients than rofecoxib-treated patients (P < 0.05). The difference between diclofenac and placebo, although numerically higher for diclofenac, did not achieve statistical significance. The most common adverse events (occurring in 25% of patients in any treatment group) were headache, nausea, dizziness, postextraction alveolitis, vomiting, and pharyngitis (Table III). There were no significant between-group differences in the incidence of any of these adverse experiences.
DISCUSSION The postoperative dental-impaction pain model is a well-validated and sensitive model for assessing the efficacy of analgesic drugs in humans.‘* This dental pain study demonstrated that a single dose of rofecoxib 50 mg was superior in overall analgesic efficacy compared with a single dose of enteric-coated diclofenac sodium 50 mg over an 8-hour period as well as 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours) over a 24hour period. The overall efficacy was determined by TOPAR, which is the sum of time-weighted pain relief scores over the specified time intervals, as well as by patient global assessments at 8 and 24 hours. Other standard measures of analgesic
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Table III. Number (%) of patients with specific clinical adverse experience 25% of any treatment group.* Rofecoxib (50 mg) (n = 121) Headache Nausea Dizziness Postextraction alveolitis Vomiting Pharyngitis *There were no significant
21 (17.4) 14 (11.6) 5 (4.1) 7 (5.8) 2 (1.7) 1 (0.8) differences
32 21 9 9 6 6
(26.4) (17.4) (7.4) (7.4) (5.0) (5.0)
in
Placebo (n = 63) 18 (28.6) 10 (15.9) 5 (7.9) 3 (4.8) 7 (11.1) 2 (3.2)
among the treatment groups.
efficacy---onset of effect, peak effect, and duration of effect-also demonstrated a significantly greater effect for rofecoxib compared with enteric-coated diclofenac sodium. Similarly, other single-dose dental pain studies have suggested that enteric-coated diclofenac sodium may not be as effective in treating acute pain as other NSAIDs including naproxen 500 mg, l4 flurbiprofen 100 mg,21 and aspirin 650 mg.12 Consistent with prior acute dental pain studies2,5,6 in which the onset of analgesic effect for rofecoxib occurred within 45 minutes, the current study demonstrated that patients treated with rofecoxib achieved confirmed perceptible pain relief at 31 minutes. The onset of effect for enteric-coated diclofenac sodium was significantly slower than for rofecoxib, which supports prior acute dental pain studies showing the slower onset of entericcoated diclofenac sodium 50 mg compared with flurbiprofen 100 mg2i and enteric-coated diclofenac sodium 75 mg compared with naproxen 500 mg.i4 To address the issue of a slower analgesic onset of enteric-coated diclofenac sodium
500
Diclofenac Sodium (50 m8 q8h) (n = 121)
occurring
compared with rofecoxib, a post-hoc exploratory analysis was performed using pain scores from all the times, including those provided after rescue medication was taken. Applying this secondary approach to the data analysis, TOPARS and TOPAR results were significantly greater for enteric-coated diclofenac sodium than for placebo. Both TOPARS and TOPAR were still significantly greater for rofecoxib than for entericcoated diclofenac sodium and placebo. The differences among the groups favoring rofecoxib persisted even though the percentage of patients requiring rescue medication was more than 3 times greater for enteric-coated diclofenac sodium than for rofecoxib over 8 hours (66.9% vs 19.8%; P c 0.001) and more than 2.5 times greater for enteric-coated diclofenac sodium than for rofecoxib over 24 hours (76.0% vs 28.9%; P < 0.001). This analysis also demonstrated that enteric-coated diclofenac sodium did, in fact, have a significantly greater analgesic effect than placebo, which is in agreement with prior acute dental pain studies l&l3 of orally administered, enteric-coated diclofenac sodium 50 mg.
D.J. CHANG ET AL.
The enteric coating of diclofenac sodium may have contributed to the delayed onset of analgesic effect. Other formulations of diclofenac, including intravenous diclofenac sodium,22 oral dispersible diclofenac sodium,23,24 and oral diclofenac potassium,25326 have shown a more rapid onset of action than oral enteric-coated diclofenac sodium for postoperative dental pain. Thus any extrapolation to comparisons with these agents cannot be made. Safety assessment showed that rofecoxib and enteric-coated diclofenac sodium were generally well tolerated. Only 1 serious adverse event was reported in a patient randomized to placebo. The incidences of any adverse events and drugrelated adverse events were significantly higher for enteric-coated diclofenac sodium than for rofecoxib; no statistical difference was detected between rofecoxib and placebo, although the rates were numerically higher for placebo. The higher incidence of side effects associated with enteric-coated diclofenac sodium may have been due to the higher utilization of opioid-containing rescue medication among enteric-coated diclofenac sodium-treated patients. This theory, however, is not completely supported by the examination of the placebo group, which had adverse event rates numerically lower than the enteric-coated diclofenac sodium group despite greater use of rescue opioid analgesia.
CONCLUSIONS In this study, a single dose of rofecoxib 50 mg, the recommended dose for the treatment of acute pain, provided greater overall analgesic efficacy over 8 hours (as determined by TOPAR and patient global
assessment at 8 hours), more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of action than a single dose of enteric-coated diclofenac sodium 50 mg in patients with moderate to severe pain associated with impacted third molar dental surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours (as determined by TOPAR and patient global assessment at 24 hours). When efficacy measurements recorded after patients took rescue medication were included in the analysis, a single 50-mg dose of rofecoxib still demonstrated greater overall analgesic efficacy than did a single dose of entericcoated diclofenac sodium 50 mg on TOPAR and 3 doses of enteric-coated diclofenac sodium 50 mg on TOPAR24; both rofecoxib and enteric-coated diclofenac sodium had greater overall analgesic efficacy than placebo on TOPARS and TOPAR24. Rofecoxib-treated patients experienced a lower incidence of any adverse events and drug-related adverse events than did enteric-coated diclofenac sodium-treated patients.
ACKNOWLEDGMENTS The study was funded by a grant from Merck & Co, Inc, West Point, Pennsylvania. The authors thank Drs. Janet Rush, William Keane, and John Yates for their review of the manuscript and helpful comments. The authors also would like to acknowledge the active participation of the following investigators and study staff: Yuki Morris (Project Manager), Dr. Julius Hyatt (Principal Investigator [PI], SCIREX CRC, Baltimore, Maryland), Dr. Donald
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Bandy (PI, SCIREX CRC, San Marcos, Texas), Dr. Roger Badwal (PI, SCIREX CRC, Windsor, Connecticut). Dr. Desjardins served as PI for the SCIREX CRC, Austin, Texas. The following staff served as lead clinical coordinators: Diego Ceniceros, Suzan Schwing, Janine Ritchie, and Joan LeBlanc.
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Address correspondence to: David J. Chang, MD, Merck & Co, Inc, HM 202, PO Box 4, West Point,
PA 19486-0004.
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