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acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults
CLINICAL
THERAPEUTICSWOL.
23, NO. 2,200l
Efficacy and Tolerability of Celecoxib Versus Hydrocodone/Acetaminophen in the Treatment of Pain After Ambulatory Orthopedic Surgery in Adults Joseph S. Gimbel, MD,’ Andrew Brugger, MD,2 William Zhao, PhD,2 Kenneth M. Verburg, PhD,2 and G. Steven Geis, MD, PhD2 ‘Arizona Research Center LLC, Phoenix, Arizona, and 2Research and Development, Pharmacia Corporation, Skokie, Illinois
ABSTRACT Background: Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal anti-inflammatory drugs; however, both types of medications are associated with side effects that can limit their usefulness in the outpatient setting. Objective: Two studies with identical protocols assessed the single- and multiple-dose analgesic efficacy and tolerability of celecoxib, a specific cyclooxygenase-2 inhibitor, in the treatment of acute pain after orthopedic surgery. Methods: These were multicenter, randomized, placebo- and active-controlled, doubleblind, parallel-group trials conducted between January and June 1998. Both consisted of a single-dose assessment period (SDAP) and a multiple-dose assessment period (MDAP). In the SDAP, patients who had undergone orthopedic surgery received a single oral dose of celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo within 24 hours after the end of anesthesia, with pain assessments conducted over the following 8hour period. In the MDAP, extending from 8 hours after the first dose of study medication up to 5 days, patients who had received 51 dose of rescue medication during the SDAP continued on study medication (placebo recipients were rerandomized to active treatment), which could be taken up to 3 times a day as needed. Results: A total of 418 patients were enrolled in the 2 trials. During the SDAP, 141 patients received celecoxib, 136 received hydrocodone/acetaminophen, and 141 received placebo. During the MDAP, 185 patients received celecoxib and 18 1 received hydrocodone/ acetaminophen. When the combined data were analyzed, mean pain intensity difference (PID) scores generally favored the active treatments over placebo from 1 to 6 hours (with the exception of 1.5 hours) after dosing (P s 0.016) and favored celecoxib over the other Accepted
for publication
December 20, 2000.
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J.S. GIMBEL ET AL.
treatments at 7 and 8 hours after dosing (P < 0.001). The active treatments demonstrated superior summed PID scores through 8 hours (P c O.OOl), significantly shorter median times to onset of analgesia (P < O.OS), and significantly longer median times to first use of rescue medication (P < 0.05). During the MDAP, more hydrocodonelacetaminophen-treated patients (20%) than celecoxib-treated patients (12%) required rescue medication (P < 0.05), and the celecoxib group had significantly lower maximum pain intensity scores (P < 0.001, days 2-5), required fewer doses of study medication (P 5 0.01, days 3-5), and had superior scores on a modified American Pain Society Patient Outcome Questionnaire (P zz 0.013). In addition, a significantly lower proportion of celecoxib-treated patients experienced adverse events (43%) compared with hydrocodone/acetaminophen-treated patients (89%; P < 0.001). Conclusions: Over 8 hours, patients with moderate to severe pain after orthopedic surgery experienced comparable analgesia with single doses of celecoxib and hydrocodonelacetaminophen. Over a 5-day period, oral doses of celecoxib 200 mg taken 3 times a day demonstrated superior analgesia and tolerability compared with hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day. Most patients required no more than 2 daily doses of celecoxib 200 mg for the control of their postorthopedic surgical pain. Key words: celecoxib, COX-2, opioid analgesic, postoperative pain, clinical trial. (Clin Thel: 2001;23:228-241)
INTRODUCTION Outpatient orthopedic procedures are associated with moderate to severe postop-
erative pain, and ambulatory surgery requires effective control of postoperative pain with oral analgesics after hospital discharge. L2 Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal antiinflammatory drugs (NSAIDs); however, both types of medications are associated with side effects that can limit their usefulness in the outpatient setting. Side effects of opioids, such as nausea, vomiting, constipation, respiratory depression, and sedation, can be problematic in some patients.3 Although NSAIDs are effective alternatives to opioid medications for mild to moderate pain after ambulatory surgical procedures, they are associated with potentially serious side effects, including gastrointestinal (GI) hemorrhage and ulceration, and alteration of platelet function.4q5 Traditional NSAIDs exert their analgesic and anti-inflammatory effects through inhibition of the enzyme cyclooxygenase (COX). Two isoforms of COX have been identified-COX1, a constitutive form, and COX-2, an inducible form that is associated with inflammation and pain.6 Traditional NSAIDs inhibit both isozymes by the same mechanism, resulting in nonselective, or concomitant, inhibition of COX-1 and COX-2.6 In contrast, there is in vitro, in vivo, biochemical, and clinical evidence that celecoxib* is a specific inhibitor of COX-2.’ In vitro, celecoxib has an -375-fold greater affinity for COX-2 than for COX-l.8 Inhibition of COX-2 without inhibition of COX-1 provides analgesic and anti-inflammatory activity without concomitant impairment of normal COX- l-mediated physiologic functions of the GI tract and platelets.9-13 Re*Trademark: Celebrex@ Skokie, Illinois).
(Pharmacia
Corporation,
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nal tolerability has also been demonstrated in recent clinical studies. 14,i5 Clinical trials with celecoxib have demonstrated that it is effective in the treatment of chronic pain in patients with rheumatoid arthritis and osteoarthritis.16-18 In patients with moderate to severe postsurgical dental pain, celecoxib dosed at 100 to 400 mg has been shown to provide clinically significant pain relief throughout an &hour postdose assessment period.19 The studies described in this paper assessed the efficacy and tolerability of celecoxib in the treatment of acute pain after outpatient orthopedic surgery.
PATIENTS
AND METHODS
Recruitment was conducted between January and June 1998 by 24 investigators at different sites in the United States. Male and female patients aged 2 18 years were eligible for the study if they had undergone uncomplicated orthopedic surgery that required open manipulation of bone with periosteal elevation, including bunionectomy, anterior cruciate ligament repair, open reduction and internal fixation of long-bone fractures, laminectomy, or osteotomy for acquired or congenital malformations. Entry requirements also included a baseline pain intensity score of ~45 mm on a 100~mm visual analog scale (0 mm = no pain, 100 mm = worst pain). Eligible patients had to be in satisfactory health, as determined by the investigator on the basis of medical history and physical examination. Women of childbearing potential were included if they were confirmed to be using adequate contraception, were not lactating, and had a negative pregnancy test result at baseline. Written informed consent was obtained from all patients before enrollment in the studies.
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Patients were excluded if they had undergone total hip or knee replacement or were scheduled for an additional surgical procedure that might produce greater surgical trauma than the orthopedic procedure alone. Other exclusion criteria included cognitive impairment that would preclude compliance with the protocol; inability to tolerate oral medication; a diagnosis of or treatment for esophageal, gastric, or duodenal ulceration; a history of cancer or uncontrolled chronic disease; abnormalities in aspartate transaminase, alanine transaminase, blood urea nitrogen, or creatinine levels ~1.5 times the upper limit of the reference range; or a history of hypersensitivity to any NSAID, COX-2specific inhibitor, sulfonamide, opiate, or analgesic that has cross-sensitivity with the medications used in these studies. Study Design The 2 randomized, placebo- and activecontrolled, double-blind, parallel-group, multicenter trials had identical protocols. Both studies were divided into 2 assessment periods: the single-dose assessment period (SDAP), defined as the L&hour period after the first dose of study medication, and the multiple-dose assessment period (MDAP), which began 8 hours after the first dose of study medication and continued for up to 5 days. In the SDAP, patients who met the inclusion criteria were randomly assigned to 1 of 3 study arms: celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo. Hydrocodone/acetaminophen, an oral opioid analgesic indicated for the relief of moderate to severe pain, was chosen as the active comparator to confirm model sensitivity during the SDAP and to allow blinding during the MDAI?*’ The
J.S. GIMBEL ET AL.
dosage of hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day as needed was selected for use during the MDAP both to reflect the most common prescribing pattern and to compare effcacy and tolerability with celecoxib 200 mg taken 3 times a day as needed.“’ The 3times-daily dosing of celecoxib for postsurgical pain was in contrast to the onceand twice-daily regimens recommended for conditions associated with chronic pain. During the SDAP, patients received a single dose of study medication within 24 hours after the end of anesthesia. Patients could request rescue pain medication at any time during the SDAP However, once rescue medication was taken, no further pain assessments were performed during the SDAP. Patients remained at the treatment facility throughout the SDAP. Patients who had received 51 dose of rescue medication during the SDAP continued into the MDAP Those who had received hydrocodoneiacetaminophen or celecoxib during the SDAP were continued on the same active treatment in the MDAP. Placebo was not used in the MDAP. Those who had received placebo during the SDAP were rerandomized to 1 of the 2 active treatments in the MDAP. The MDAP began 8 hours after the initial dose of study medication and continued for up to 5 days. Once it was ascertained that patients were not experiencing significant side effects and they had received and understood instructions for completing the pain assessments, they were discharged from the clinic. They were allowed to begin remedication 8 hours after the initial dose of study medication and repeat the dose as often as once every 8 hours as needed, up to 3 doses per day. The medication could be taken with or without food. Patients who required res-
cue medication at any time during MDAP were withdrawn immediately.
the
EfJicacy and Tolerability Assessments The pain model used in these studies was based on draft documents issued by the US Food and Drug Administration.22.23 During the SDAP, patients assessed levels of pain intensity and pain relief at baseline (hour 0) and every 15 minutes for the first hour, at hour 1.5, and hourly from hours 2 through 8. Pain intensity was reported by patients on a scale from 0 to 3, with 0 representing no pain and 3 representing severe pain; pain relief was reported on a scale from 0 to 4, with 0 representing no relief and 4 representing complete relief. Time to the onset of perceptible pain relief and time to the onset of meaningful pain relief were assessed using 2 stopwatches started at the time of taking the first study medication. The patient was instructed to stop the first stopwatch when pain relief was first perceived and the second stopwatch when pain relief was first considered to be meaningful. Measures of efficacy for the SDAP included (1) time-specific pain intensity difference (PID), derived by subtracting pain intensity scores at a specified time point from the baseline score; (2) summed PID for the sum of the PID scores of all patients by treatment group through the first 8 hours (SPID-8); (3) time to onset of analgesia, defined as time to the onset of perceptible relief in patients who went on to experience meaningful pain relief; and (4) time to first use of rescue medication. During the MDAP, assessments of maximum pain intensity and maximum pain relief during the preceding 24 hours were completed at bedtime on each full treat-
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CLINICAL THERAPEUTICS”
ment day for up to 5 days, and just before taking rescue medication, if used. Patients used a diary to record the number of doses taken each day and the time each dose was taken. A trained observer telephoned patients each day to ensure compliance and adequate pain relief. A modified American Pain Society (APS) patient outcome questionnaire, consisting of 3 relevant measures of pain and 6 measures of pain interference from the original questionnaire,24 was completed at the end of the MDAP. All 9 measures are based on a scale from 0 to 10, with 0 signifying no pain or no interference and 10 signifying worst pain or worst interference. Pain measures included pain right now, worst pain in 4 days, and average level of pain in 4 days. Measures of interference included the amount to which pain interfered with general activity, mood, walking ability, relations with others, sleep, and enjoyment of life. Measures of efficacy for the MDAP included (1) the proportion of patients who completed the MDAP; (2) maximum pain intensity in the past 24 hours for days 2 to 5; and (3) number of doses of study medication taken per day on days 2 to 5. Days during the MDAP were counted using calendar days. Tolerability was assessed during the SDAP and MDAP by determining the proportion of patients who reported rl adverse event and the overall frequency and severity of adverse events.
Statistical Analysis The modified intent-to-treat (ITT) cohort included all patients in both studies who took ~1 dose of study medication, excluding those who dropped out
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secutive pain assessments were missing within the first 2 hours of the study. All statistical analyses for efficacy during the SDAP were performed on data from the modified ITT cohort. All statistical analyses for efficacy during the MDAP were performed on data from all patients who entered the MDAP. Summary statistics for all randomized patients in both studies were tabulated by treatment group. Treatment groups were compared using the chi-square test for categoric variables and 2-way analysis of variance (ANOVA) with treatment effects or the Wilcoxon rank sum test, as appropriate, for continuous variables. Baseline categoric variables were compared to examine homogeneity with regard to surgical procedures and pain intensity ratings using the CochranMantel-Haenszel test stratified by center. Continuous baseline variables were tested using 2-way ANOVA. Time-specific PID and SPID-8 were analyzed by ANOVA, with treatment, center, and pain intensity at baseline (hour 0) as factors. The Fisher protected leastsignificant-difference multiple comparisons procedure was applied to the leastsquare treatment means. Time to onset of analgesia and time to use of rescue medication were analyzed using survival analysis methods.25,26 For time to onset of analgesia, patients were censored at hour 8 if the second stopwatch had not been stopped. For time to use of rescue medication, patients who did not receive rescue medication were considered censored at 8 hours. Patients who dropped out and did not receive rescue medication were censored at the time of dropout. Patients who took rescue medication were assigned a time by subtracting the time the dose of study medication
J.S. GIMBEL ET AL,
was taken from the time at which rescue medication was taken.
RESULTS Single-Dose Assessment Period Four hundred eighteen patients were randomized to the SDAP treatment groups and received rl dose of study medication, including 141 patients receiving celecoxib 200 mg, 136 patients receiving hydroco-
Table I. Patient characteristics
during the 2 study periods.
Single-dose assessment period Age (mean k SD), y Sex, no. (%)* Female Male Surgical procedure, no. (%)* Bunionectomy Anterior cruciate ligament repair Fixation of long-bone fractures Laminectomy Osteotomy Other orthopedic procedure Other Baseline pain intensity* Categoric rating+ Moderate Severe Visual analog scale (mean f SD) Multiple-dose assessment period Age (mean f SD), y Sex, no. (%) Female Male NA = not applicable. *In some categories, percentages ‘One patient receiving celecoxib
done 10 mg/acetaminophen 1000 mg, and 141 patients receiving placebo. Baseline characteristics, including age, sex, type of surgical procedure, and baseline pain intensity, were comparable between groups (Table I). More celecoxib patients completed the SDAP than did hydrocodone/acetaminophen or placebo patients, and fewer celecoxib patients required rescue medication during the SDAP (P < 0.05). Fifty-five percent of celecoxib patients completed
Celecoxib 200 mg (n = 141)
Hydrocodone 10 mg/ Acetaminophen 1000 mg (n = 136)
Placebo (n = 141)
47.4 + 15.0
43.9 f 15.2
45.2 + 16.0
84 (60) 57 (40)
85 (63) 51 (38)
84 (60) 57 (40)
19 (13)
19 (14) 13 (10)
28 (20)
7 (5)
9 (6) 93 (66)
0 (0) 12 (9) 0 (0) 11 (8) 81 (60)
12 (9) 0 (0) 13 (9) 3 (2) 7 (5) 78 (55)
88 (62) 52 (37) 65.5 f 16.5
98 (72) 38 (28) 62.8 f 16.5
83 (59) 58 (41) 65.5 k 15.3
46.6 + 15.2
44.4 2 16.1
NA
107 (58) 78 (42)
114 (63) 67 (37)
NA NA
1 (1) 11 (8) l(l)
do not total 100 due to rounding error. bad no baseline pain intensity rating entered on the case report form.
233
CLINICAL THERAPEUTICS”
group compared with the hydrocodonel acetaminophen and placebo groups (P < 0.001 at 7 and 8 hours). SPID-8 scores for the active treatments were significantly superior to those for placebo (P < 0.001) (Figure 2).
the SDAP period, compared
with 48% of the hydrocodonelacetaminophen group and 36% of the placebo group. Two patients were withdrawn from the study during the SDAP because of adverse events, and the remaining patients were withdrawn because they received rescue medication. Details of patient disposition are listed in Table II.
Onset of Analgesia Compared with placebo, the active treatments demonstrated superiority on measures of onset of analgesia, including the percentage of patients achieving analgesia and the median time to onset of analgesia. Only 45% of the placebo group achieved analgesia, compared with 64% and 75% of celecoxib patients and hydrocodone/acetaminophen patients, respectively (P < 0.05). The median times to onset of analgesia in the celecoxib and hydrocodonelacetaminophen patients were significantly shorter (35 and 31 minutes,
Pain Intensity DifSerence The celecoxib and hydrocodone/acetaminophen treatments were superior to placebo on most time-specific PID scores (Figure 1). As early as 1 hour postdose, mean PID scores significantly favored celecoxib and hydrocodonelacetaminophen (P s 0.016 at 2-6 hours, except at 1.5 hours in the celecoxib group). At 7 and 8 hours postdose, mean PID scores were significantly superior in the celecoxib Table II. Patient disposition.
Celecoxib 200 mg
Hydrocodone 10 mg/ Acetaminophen 1000 mg
Placebo
P
Single-dose assessment period (SDAP), no. (%) All randomized SDAP patients Withdrawal due to adverse event Patients with ~1 event Patients requiring 2 1 dose of rescue medication Multiple-dose assessment period (MDAP), no. (%)* All randomized MDAP patients Withdrawal due to adverse event Patients with rl event Patients requiring 2 1 dose of rescue medication Lost to follow-up Protocol noncompliance *No patient received placebo during the MDAP.
234
141
136
141
l(1) 16 (11)
l(1) 37 (27)
0 (0) 20 (14)
0.002
62 (44)
70 (51)
90(64)
0.003
185
181
4 (2) 62 (34)
7 (4) 143 (79)
22 (12)
36 (20)
l(1) l(1)
0 (0) 3 (2)
J.S. GIMBEL ET AL.
A Celecoxib 200 mg A Hydrocodone IO mg/acetaminophen 0 Placebo
01
1000 mg
,,,,I,,IIIIIlIII
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
6
Time (h)
Figure
1. Mean pain intensity difference (PID) scores over time during the single-dose assessment period. The visual analog scale ranged from 0 to 3, with 3 representing the worst pain. *P c 0.05, celecoxib and hydrocodone/acetaminophen versus placebo; +P < 0.05, celecoxib versus hydrocodone/acetaminophen and placebo.
-
I_
Celecoxib 200 mg
Hydrocodone 10 mg/ Acetaminophen 1000 mg
Placebo
Figure 2. Summed pain intensity difference scores through 8 hours (SPID-8) during the single-dose assessment period. The visual analog scale ranged from 0 to 3, with 3 representing the worst pain. *P< 0.001, celecoxib and hydrocodone/acetaminophen versus placebo. 235
CLINICAL THERAPEUTICS”
respectively) than in the placebo (>8 hours, P < 0.05).
group
Use of Rescue Medication The median times to first use of rescue medication in the celecoxib and hydrocodone/acetaminophen patients were significantly longer (>8 hours and 7 hours 25 minutes, respectively) than in the placebo group (3 hours 52 minutes; P < 0.05). Fifty-one percent of hydrocodonel acetaminophen patients and 64% of placebo patients required rl dose of rescue medication. In comparison, only 44% of celecoxib patients required rescue medication, despite the fact that more celecoxib patients than hydrocodone/ acetaminophen patients experienced “severe” versus “moderate” baseline pain (P = 0.003 between the 3 groups).
Multiple-Dose
Assessment
Period
Of the 418 patients randomized to the SDAP, 366 continued to the MDAP. During this period, 185 patients were rerandomized to celecoxib (107 women, 78 men), including 129 who had received celecoxib during the SDAP and 56 who had received placebo; 181 patients were rerandomized to hydrocodone/acetaminophen (114 women, 67 men), including 124 who had received hydrocodonelacetaminophen during the SDAP and 57 who had received placebo. There were no significant between-group differences in baseline characteristics, including age and sex (Table I). More celecoxib patients than hydrocodone/acetaminophen patients completed the MDAP and thus the overall study, and fewer celecoxib patients required rescue medication during the
236
(Table II). During this period, 12% of celecoxib patients, compared with 20% of the hydrocodonelacetaminophen patients, required 2 1 dose of rescue medication (P = 0.05). MDAP
Maximum Pain Intensity At the end of each day of the MDAP, the celecoxib group had significantly superior maximum pain intensity scores compared with the hydrocodone/acetaminophen group (P < 0.001, days 2-5) (Figure 3). Number of Daily Doses of Medication On each day of the MDAP, the celecoxib group required fewer doses of study medication than did the hydrocodonej acetaminophen group. Celecoxib patients required an average of 1.9 doses on day 1 and 1.3 doses on day 5, compared with an average of 2.1 and 1.7 doses on the same days in the hydrocodonelacetaminophen group. The difference between groups was significant on days 3 through 5 (P s 0.01). By day 5,41% of patients in the celecoxib group required no analgesic medication, compared with 20% of patients in the hydrocodonelacetaminophen group. American Pain Society Outcome Measures During the MDAP, 88% of celecoxib patients and 93% of hydrocodonel acetaminophen patients reported that they had experienced pain over the preceding 4 days. The celecoxib group had statistically superior scores on each of the 9 measures in the modified APS assessment (P s 0.013) (Figure 4). The composite pain interference score was significantly more favorable in the celecoxib patients (17.8) than in the hydrocodone/acetaminophen patients (24.8; P = 0.001).
J.S. GIMBEL ET AL. 3.0 c! 8 2.5 ul .z? g 2 2.0 & .E $ 1.5 E z ‘3
1.0
5 s a,
0.5
r 0
n Celecoxib 200 mg 0 Hydrocodone 10 mg/ acetaminophen 1000 mg
I l
l
l-7 *
T 1
2
3
4 Day
Figure 3. Mean maximum pain intensity scores on days 2 through 5 during the multipledose assessment period. The rating scale ranged from 0 to 3, with 3 representing severe pain. *P < 0.001, celecoxib versus hydrocodone/acetaminophen.
W Celecoxib 200 mg
Pain right now
0 Hydrocodone 10 mg/ acetaminophen 1000 mg
Worst pain in 4 days Average pain level over 4 days General activity Mood Walking ability Relations with others Sleep Enjoyment
of life I 0
1
I
I
2 3 American
I
I
I
I
I
I
4 5 6 7 6 9 Pain Society Measure
I
10
Figure 4. Scores on American Pain Society measures at day 5. For each measure, the rating scale ranged from 0 to 10, with 10 representing worst pain or worst interference. *P 5 0.013, celecoxib versus hydrocodone/acetaminophen. 237
CLINICAL
Table III. Cumulative adverse events in the single- and multiple-dose randomized patients.*
Adverse Event Patients with ~1 event Nausea Headache Somnolence Vomiting Dizziness Dyspepsia Dry mouth Pruritus Constipation
assessment periods, all
Celecoxib 200 mg (n = 195)
Hydrocodone 10 mg/ Acetaminophen 1000 mg (n = 194)
87 (45) 22 (11) 20 (10) 15 (8) 10 (5) 7 (4) 7 (4) 2 (1) 2 (1) 0 (0)
125 (64) 53 (27) 23 (12) 30 (15) 17 (9) 31 (16) l(1) 5 (3) 6 (3) 6 (3)
*Totals include all patients who took 21 dose of active drug during either the single-dose the multiple-dose assessment period.
Tolerability Adverse events are listed in Table III. During the SDAP, 1 patient from each of the active-treatment groups withdrew due to adverse events. The celecoxib group had the lowest proportion of patients with rl adverse event (1 l%), followed by the placebo group (14%) and the hydrocodone/ acetaminophen group (27%) (P = 0.002 between groups). Across the SDAP and MDAP, patients who had taken ~1 dose of celecoxib had a significantly lower cumulative proportion of adverse events than patients who had taken B 1 dose of hydrocodonelacetaminophen (43% vs 89%; P < 0.001) (Table III). The most frequently reported adverse events in the celecoxib group were nausea (1 l%), headache (lo%), somnolence (8%), vomiting (5%), dizziness (4%), and dyspepsia (4%). With the exception of dyspepsia (P = 0.068), all of these events were observed in a greater proportion of patients in the
238
THERAPEUTICS”
P
0.015 assessment
period or
hydrocodonelacetaminophen group. The most commonly reported adverse events in the hydrocodonelacetaminophen group were nausea (27%; P < O.OOl), somnolence (15%; P = O.OlS), dizziness (16%; P < O.OOl), and constipation (3%; P = 0.015). During the MDAP, 4 patients from the celecoxib group and 7 patients from the hydrocodonelacetaminophen group withdrew because of adverse events. The celecoxib group had a lower proportion of patients with 21 adverse event (33%) compared with the hydrocodone/acetaminophen group (78%; P < 0.001). DISCUSSION The results of these 2 randomized, double-blind, placebo- and active-controlled trials demonstrate the clinical efficacy and tolerability of celecoxib, a COX-2-specific inhibitor, in the treatment of moderate to severe pain after outpatient orthopedic surgery. Onset of analgesia occurred
J.S. GIMBEL ET AL.
within 1 hour of the first dose of celecoxib. Pain relief was sustained through the 5 days of the study, as demonstrated on several measures of efficacy. All single-dose analgesic efficacy variables favored a single dose of celecoxib 200 mg compared with placebo. The median onset of analgesia after a single dose of celecoxib was 35 minutes. The magnitude of analgesic effect over the SDAP was similar to that with hydrocodone/acetaminophen, and the majority of patients completed this S-hour period without requiring another dose of analgesic medication. During the MDAP, measures of efficacy favored celecoxib over hydrocodone/acetaminophen. Over the 5-day period, 80% to 90% of celecoxib patients experienced satisfactory pain relief while taking an average daily dose of 200 mg twice daily without additional rescue medication. These data are consistent with the results of clinical trials in osteoarthritis, in which celecoxib 100 and 200 mg twice daily produced significant relief of acute flare pain from osteoarthritis of the hip*’ and kneel6 within 1 day of the start of treatment and demonstrated continuing efficacy for the remaining 6 days of the assessment. The present study compared the tolerability profile of celecoxib 200 mg taken 3 times a day as needed with that of a similar regimen of a mild opiate combination, hydrocodone 10 mg/acetaminophen 1000 mg. During both assessment periods and cumulatively, celecoxib patients experienced significantly fewer side effects. Cumulatively, twice as many hydrocodone/acetaminophen patients reported 81 adverse effect (eg, nausea, somnolence, dizziness, constipation). Cumulatively, nausea was reported -2.5 times more frequently and dizziness 4 times more frequently in patients treated with hydrocodonelacetaminophen than with
celecoxib. Approximately twice as many hydrocodone/acetaminophen-treated patients reported vomiting and somnolence. Constipation was reported by hydrocodone/ acetaminophen-treated patients but not celecoxib-treated patients. Opioids such as hydrocodone are known to have physiologic properties that alter gastric motility. As a class, they also are known to produce respiratory depression, alteration in mood, physical tolerance, and dose-dependent bradycardia.28 The conditions of the MDAP parallel actual practice after ambulatory orthopedic surgery. Specifically, after undergoing a variety of outpatient procedures, including laminectomy, arthroscopy, and foot surgery, patients were discharged home and allowed to take blinded study medication on an asneeded basis up to 3 times a day. If this was not sufficient to control their pain, they were allowed to take rescue medication, but their participation in the study was discontinued once they did so. A majority of patients required only 2 daily doses of celecoxib 200 mg to manage acute postoperative pain, and the results suggest that the majority achieved satisfactory pain control with few adverse events.
CONCLUSIONS In this study, celecoxib 200 mg was well tolerated taken in single oral doses as needed up to 3 times a day over a 5-day period. The single dose displayed analgesic efficacy in patients with moderate to severe pain after outpatient orthopedic surgery. Taken at a minimum interval of 8 hours over a 5-day period, celecoxib 200 mg displayed analgesic efficacy similar or superior to that of a similar regimen of hydrocodonelacetaminophen. Most patients required only twice-daily doses of
239
CLINICAL THERAPEUTICS”
celecoxib 200 mg to control their acute pain after orthopedic surgery.
ACKNOWLEDGMENTS The following investigators participated in this trial: Steven Belknap, MD, Peoria, Illinois; Nelson G. Botwinick, MD, New York, New York; O.F. Cannon, Jr., MD, Ocala, Florida; Stephen E. Daniels, DO, Austin, Texas; Christopher M. Fallows, DO, Inverness, Florida; Joseph S. Gimbel, MD, Glendale, Arizona; Stephen F. Gordon, MD, Atlanta, Georgia; Marc Z. Hammerman, MD, Hollywood, Florida; Stephen J. Hawes, Jr., MD, Charlotte, North Carolina; W. John Henry III, MD, Greer, South Carolina; Thurman E. Hunt, MD, Newark, New Jersey; Michael Kentor, MD, Pittsburgh, Pennsylvania; Alan J. Kivitz, MD, Altoona, Pennsylvania; Richard M. Konsens, MD, Orlando, Florida; Leonard I. Kraut, MD, Lakewood, New Jersey; Paul Lunseth, MD, Tampa, Florida; Daryl K. MacCarter, MD, Denver, Colorado; Margaret Michalska, MD, Chicago, Illinois; Stephen H. Miller, MD, Las Vegas, Nevada; Robert J. Noveck, MD, PhD, New Orleans, Louisiana; Jon Sanchez, MD, Springfield, Montana; Paul F. Siami, MD, Evansville, Indiana; Randall R. Stoltz, MD, Evansville, Indiana; and B. King Tipton, MD, Fort Myers, Florida.
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6. Vane JR. Inhibition of prostaglandin
synthesis as a mechanism of action for the aspirin-like drugs. Nature. 197 I;23 1:232-
235. 7. Verburg KM, Maziasz TJ, Weiner E, et al. COX-2 specific inhibitors: Definition of a new therapeutic concept. Am J Ther. In press. 8. Penning TD, Talley JJ, Bertenshaw SR, et al. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-1-yllbenzenesulfonamide (SC-58635, celecoxib). J Med Chem. 1997;40: 13471365. 9. Dewitt DL, Meade EA, Smith WL. PGH synthase isoenzyme selectivity: The potential for safer nonsteroidal antiinflammatory drugs. Am J Med. 1993;95:40%448. 10. Bensen WG, Zhao SZ, Burke TA, et al. Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo. J Rheumatol. 2000;27: 1876-l 883. 11. Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol. 2000;95: 1681-1690.
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12. Leese PT, Hubbard RC, Karim A, et al. Effects of celecoxib, a novel cyclooxygen-
ase-2 inhibitor, on platelet function in healthy adults: A randomized, controlled trial. J Clin Phannacol. 2000;40: 124-l 32. in non13. Singh G. Recent considerations steroidal anti-inflammatory drug gastropathy. Am J Med. 3998;105:313-38s. 14. Whelton A, Maurath CJ, Verburg KM, Geis GS. Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J The,: 2000;7:159-175. 15. Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med. 2000;160:1465-1470. 16. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: A randomized controlled trial. Mayo Clin Proc. 1999;74:1095-1105. 17. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: A randomized controlled trial. JAMA. 1999;282:1921-1928. 18. Williams GW, Ettlinger RE, Ruderman EM, et al. Treatment of osteoarthritis with a once-daily dosing regimen of celecoxib: A randomized controlled trial. J Clin Rheumatol. 2000;6:65-74. 19. Hubbard RC, Mehlisch DR, Jasper DR, et al. SC-58635, a highly selective inhibitor of COX-2, is an effective analgesic in an acute post-surgical pain model. J Invest Med. 1996;44;293A. Abstract.
20. VicodinTM (hydrocodone 5 mg/acetaminophen 500 mg) tablets prescribing information. Physicians ’ Desk Reference@. Montvale, NJ: Medical Economics; 1999: 1366-1367. 21. Physician Drug Diagnosis Audit. Newtown, Pa: Scott-Levin Inc; 1999. 22. Presentation of Eficacy Results of SingleDose Analgesics for Studies Using Acute Pain Models. FDA Draft Document, June 1997. 23. Guideline for the Clinical Evaluation of Analgesic Drugs. US Department of Health and Human Services, US Food and Drug Administration, Revised December 1992. 24. American Pain Society Quality of Care Committee. Quality improvement guidelines for the treatment of acute pain and cancer pain. JAMA. 1995;274:1874-1880. 25. Miller RG. Survival Analysis. New York: John Wiley & Sons; 1981. 26. Simon R, Lee YJ. Nonparametric contidence limits for survival probabilities and median survival time. Cancer Treat Rep. 1982;66:3742. 27. Sunshine A, Moskowitz R, Woods E, et al. Efficacy of celecoxib in treating acute flare pain in osteoarthritis of the hip. In: Program and abstracts of the 9th World Congress on Pain; August 22-27, 1999; Vienna, Austria. Abstract 248. 28. Ferrante FM. Principles of opioid pharmacotherapy: Practical implications of basic mechanisms. J Pain Symptom Manage. 1996;11:265-273.
Address correspondence to: Joseph S. Gimhel, MD, Medical Director, Arizona Research Center LLC, 2525 W. Greenway Road, Suite 114, Phoenix, AZ 85023. E-mail: [email protected]
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23, NO. 2,200l
Efficacy and Tolerability of Celecoxib Versus Hydrocodone/Acetaminophen in the Treatment of Pain After Ambulatory Orthopedic Surgery in Adults Joseph S. Gimbel, MD,’ Andrew Brugger, MD,2 William Zhao, PhD,2 Kenneth M. Verburg, PhD,2 and G. Steven Geis, MD, PhD2 ‘Arizona Research Center LLC, Phoenix, Arizona, and 2Research and Development, Pharmacia Corporation, Skokie, Illinois
ABSTRACT Background: Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal anti-inflammatory drugs; however, both types of medications are associated with side effects that can limit their usefulness in the outpatient setting. Objective: Two studies with identical protocols assessed the single- and multiple-dose analgesic efficacy and tolerability of celecoxib, a specific cyclooxygenase-2 inhibitor, in the treatment of acute pain after orthopedic surgery. Methods: These were multicenter, randomized, placebo- and active-controlled, doubleblind, parallel-group trials conducted between January and June 1998. Both consisted of a single-dose assessment period (SDAP) and a multiple-dose assessment period (MDAP). In the SDAP, patients who had undergone orthopedic surgery received a single oral dose of celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo within 24 hours after the end of anesthesia, with pain assessments conducted over the following 8hour period. In the MDAP, extending from 8 hours after the first dose of study medication up to 5 days, patients who had received 51 dose of rescue medication during the SDAP continued on study medication (placebo recipients were rerandomized to active treatment), which could be taken up to 3 times a day as needed. Results: A total of 418 patients were enrolled in the 2 trials. During the SDAP, 141 patients received celecoxib, 136 received hydrocodone/acetaminophen, and 141 received placebo. During the MDAP, 185 patients received celecoxib and 18 1 received hydrocodone/ acetaminophen. When the combined data were analyzed, mean pain intensity difference (PID) scores generally favored the active treatments over placebo from 1 to 6 hours (with the exception of 1.5 hours) after dosing (P s 0.016) and favored celecoxib over the other Accepted
for publication
December 20, 2000.
Printed in the USA. Reproduction
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0149-2918/01/$19.00
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treatments at 7 and 8 hours after dosing (P < 0.001). The active treatments demonstrated superior summed PID scores through 8 hours (P c O.OOl), significantly shorter median times to onset of analgesia (P < O.OS), and significantly longer median times to first use of rescue medication (P < 0.05). During the MDAP, more hydrocodonelacetaminophen-treated patients (20%) than celecoxib-treated patients (12%) required rescue medication (P < 0.05), and the celecoxib group had significantly lower maximum pain intensity scores (P < 0.001, days 2-5), required fewer doses of study medication (P 5 0.01, days 3-5), and had superior scores on a modified American Pain Society Patient Outcome Questionnaire (P zz 0.013). In addition, a significantly lower proportion of celecoxib-treated patients experienced adverse events (43%) compared with hydrocodone/acetaminophen-treated patients (89%; P < 0.001). Conclusions: Over 8 hours, patients with moderate to severe pain after orthopedic surgery experienced comparable analgesia with single doses of celecoxib and hydrocodonelacetaminophen. Over a 5-day period, oral doses of celecoxib 200 mg taken 3 times a day demonstrated superior analgesia and tolerability compared with hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day. Most patients required no more than 2 daily doses of celecoxib 200 mg for the control of their postorthopedic surgical pain. Key words: celecoxib, COX-2, opioid analgesic, postoperative pain, clinical trial. (Clin Thel: 2001;23:228-241)
INTRODUCTION Outpatient orthopedic procedures are associated with moderate to severe postop-
erative pain, and ambulatory surgery requires effective control of postoperative pain with oral analgesics after hospital discharge. L2 Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal antiinflammatory drugs (NSAIDs); however, both types of medications are associated with side effects that can limit their usefulness in the outpatient setting. Side effects of opioids, such as nausea, vomiting, constipation, respiratory depression, and sedation, can be problematic in some patients.3 Although NSAIDs are effective alternatives to opioid medications for mild to moderate pain after ambulatory surgical procedures, they are associated with potentially serious side effects, including gastrointestinal (GI) hemorrhage and ulceration, and alteration of platelet function.4q5 Traditional NSAIDs exert their analgesic and anti-inflammatory effects through inhibition of the enzyme cyclooxygenase (COX). Two isoforms of COX have been identified-COX1, a constitutive form, and COX-2, an inducible form that is associated with inflammation and pain.6 Traditional NSAIDs inhibit both isozymes by the same mechanism, resulting in nonselective, or concomitant, inhibition of COX-1 and COX-2.6 In contrast, there is in vitro, in vivo, biochemical, and clinical evidence that celecoxib* is a specific inhibitor of COX-2.’ In vitro, celecoxib has an -375-fold greater affinity for COX-2 than for COX-l.8 Inhibition of COX-2 without inhibition of COX-1 provides analgesic and anti-inflammatory activity without concomitant impairment of normal COX- l-mediated physiologic functions of the GI tract and platelets.9-13 Re*Trademark: Celebrex@ Skokie, Illinois).
(Pharmacia
Corporation,
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CLINICAL THERAPEUTICS@
nal tolerability has also been demonstrated in recent clinical studies. 14,i5 Clinical trials with celecoxib have demonstrated that it is effective in the treatment of chronic pain in patients with rheumatoid arthritis and osteoarthritis.16-18 In patients with moderate to severe postsurgical dental pain, celecoxib dosed at 100 to 400 mg has been shown to provide clinically significant pain relief throughout an &hour postdose assessment period.19 The studies described in this paper assessed the efficacy and tolerability of celecoxib in the treatment of acute pain after outpatient orthopedic surgery.
PATIENTS
AND METHODS
Recruitment was conducted between January and June 1998 by 24 investigators at different sites in the United States. Male and female patients aged 2 18 years were eligible for the study if they had undergone uncomplicated orthopedic surgery that required open manipulation of bone with periosteal elevation, including bunionectomy, anterior cruciate ligament repair, open reduction and internal fixation of long-bone fractures, laminectomy, or osteotomy for acquired or congenital malformations. Entry requirements also included a baseline pain intensity score of ~45 mm on a 100~mm visual analog scale (0 mm = no pain, 100 mm = worst pain). Eligible patients had to be in satisfactory health, as determined by the investigator on the basis of medical history and physical examination. Women of childbearing potential were included if they were confirmed to be using adequate contraception, were not lactating, and had a negative pregnancy test result at baseline. Written informed consent was obtained from all patients before enrollment in the studies.
230
Patients were excluded if they had undergone total hip or knee replacement or were scheduled for an additional surgical procedure that might produce greater surgical trauma than the orthopedic procedure alone. Other exclusion criteria included cognitive impairment that would preclude compliance with the protocol; inability to tolerate oral medication; a diagnosis of or treatment for esophageal, gastric, or duodenal ulceration; a history of cancer or uncontrolled chronic disease; abnormalities in aspartate transaminase, alanine transaminase, blood urea nitrogen, or creatinine levels ~1.5 times the upper limit of the reference range; or a history of hypersensitivity to any NSAID, COX-2specific inhibitor, sulfonamide, opiate, or analgesic that has cross-sensitivity with the medications used in these studies. Study Design The 2 randomized, placebo- and activecontrolled, double-blind, parallel-group, multicenter trials had identical protocols. Both studies were divided into 2 assessment periods: the single-dose assessment period (SDAP), defined as the L&hour period after the first dose of study medication, and the multiple-dose assessment period (MDAP), which began 8 hours after the first dose of study medication and continued for up to 5 days. In the SDAP, patients who met the inclusion criteria were randomly assigned to 1 of 3 study arms: celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo. Hydrocodone/acetaminophen, an oral opioid analgesic indicated for the relief of moderate to severe pain, was chosen as the active comparator to confirm model sensitivity during the SDAP and to allow blinding during the MDAI?*’ The
J.S. GIMBEL ET AL.
dosage of hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day as needed was selected for use during the MDAP both to reflect the most common prescribing pattern and to compare effcacy and tolerability with celecoxib 200 mg taken 3 times a day as needed.“’ The 3times-daily dosing of celecoxib for postsurgical pain was in contrast to the onceand twice-daily regimens recommended for conditions associated with chronic pain. During the SDAP, patients received a single dose of study medication within 24 hours after the end of anesthesia. Patients could request rescue pain medication at any time during the SDAP However, once rescue medication was taken, no further pain assessments were performed during the SDAP. Patients remained at the treatment facility throughout the SDAP. Patients who had received 51 dose of rescue medication during the SDAP continued into the MDAP Those who had received hydrocodoneiacetaminophen or celecoxib during the SDAP were continued on the same active treatment in the MDAP. Placebo was not used in the MDAP. Those who had received placebo during the SDAP were rerandomized to 1 of the 2 active treatments in the MDAP. The MDAP began 8 hours after the initial dose of study medication and continued for up to 5 days. Once it was ascertained that patients were not experiencing significant side effects and they had received and understood instructions for completing the pain assessments, they were discharged from the clinic. They were allowed to begin remedication 8 hours after the initial dose of study medication and repeat the dose as often as once every 8 hours as needed, up to 3 doses per day. The medication could be taken with or without food. Patients who required res-
cue medication at any time during MDAP were withdrawn immediately.
the
EfJicacy and Tolerability Assessments The pain model used in these studies was based on draft documents issued by the US Food and Drug Administration.22.23 During the SDAP, patients assessed levels of pain intensity and pain relief at baseline (hour 0) and every 15 minutes for the first hour, at hour 1.5, and hourly from hours 2 through 8. Pain intensity was reported by patients on a scale from 0 to 3, with 0 representing no pain and 3 representing severe pain; pain relief was reported on a scale from 0 to 4, with 0 representing no relief and 4 representing complete relief. Time to the onset of perceptible pain relief and time to the onset of meaningful pain relief were assessed using 2 stopwatches started at the time of taking the first study medication. The patient was instructed to stop the first stopwatch when pain relief was first perceived and the second stopwatch when pain relief was first considered to be meaningful. Measures of efficacy for the SDAP included (1) time-specific pain intensity difference (PID), derived by subtracting pain intensity scores at a specified time point from the baseline score; (2) summed PID for the sum of the PID scores of all patients by treatment group through the first 8 hours (SPID-8); (3) time to onset of analgesia, defined as time to the onset of perceptible relief in patients who went on to experience meaningful pain relief; and (4) time to first use of rescue medication. During the MDAP, assessments of maximum pain intensity and maximum pain relief during the preceding 24 hours were completed at bedtime on each full treat-
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ment day for up to 5 days, and just before taking rescue medication, if used. Patients used a diary to record the number of doses taken each day and the time each dose was taken. A trained observer telephoned patients each day to ensure compliance and adequate pain relief. A modified American Pain Society (APS) patient outcome questionnaire, consisting of 3 relevant measures of pain and 6 measures of pain interference from the original questionnaire,24 was completed at the end of the MDAP. All 9 measures are based on a scale from 0 to 10, with 0 signifying no pain or no interference and 10 signifying worst pain or worst interference. Pain measures included pain right now, worst pain in 4 days, and average level of pain in 4 days. Measures of interference included the amount to which pain interfered with general activity, mood, walking ability, relations with others, sleep, and enjoyment of life. Measures of efficacy for the MDAP included (1) the proportion of patients who completed the MDAP; (2) maximum pain intensity in the past 24 hours for days 2 to 5; and (3) number of doses of study medication taken per day on days 2 to 5. Days during the MDAP were counted using calendar days. Tolerability was assessed during the SDAP and MDAP by determining the proportion of patients who reported rl adverse event and the overall frequency and severity of adverse events.
Statistical Analysis The modified intent-to-treat (ITT) cohort included all patients in both studies who took ~1 dose of study medication, excluding those who dropped out
232
secutive pain assessments were missing within the first 2 hours of the study. All statistical analyses for efficacy during the SDAP were performed on data from the modified ITT cohort. All statistical analyses for efficacy during the MDAP were performed on data from all patients who entered the MDAP. Summary statistics for all randomized patients in both studies were tabulated by treatment group. Treatment groups were compared using the chi-square test for categoric variables and 2-way analysis of variance (ANOVA) with treatment effects or the Wilcoxon rank sum test, as appropriate, for continuous variables. Baseline categoric variables were compared to examine homogeneity with regard to surgical procedures and pain intensity ratings using the CochranMantel-Haenszel test stratified by center. Continuous baseline variables were tested using 2-way ANOVA. Time-specific PID and SPID-8 were analyzed by ANOVA, with treatment, center, and pain intensity at baseline (hour 0) as factors. The Fisher protected leastsignificant-difference multiple comparisons procedure was applied to the leastsquare treatment means. Time to onset of analgesia and time to use of rescue medication were analyzed using survival analysis methods.25,26 For time to onset of analgesia, patients were censored at hour 8 if the second stopwatch had not been stopped. For time to use of rescue medication, patients who did not receive rescue medication were considered censored at 8 hours. Patients who dropped out and did not receive rescue medication were censored at the time of dropout. Patients who took rescue medication were assigned a time by subtracting the time the dose of study medication
J.S. GIMBEL ET AL,
was taken from the time at which rescue medication was taken.
RESULTS Single-Dose Assessment Period Four hundred eighteen patients were randomized to the SDAP treatment groups and received rl dose of study medication, including 141 patients receiving celecoxib 200 mg, 136 patients receiving hydroco-
Table I. Patient characteristics
during the 2 study periods.
Single-dose assessment period Age (mean k SD), y Sex, no. (%)* Female Male Surgical procedure, no. (%)* Bunionectomy Anterior cruciate ligament repair Fixation of long-bone fractures Laminectomy Osteotomy Other orthopedic procedure Other Baseline pain intensity* Categoric rating+ Moderate Severe Visual analog scale (mean f SD) Multiple-dose assessment period Age (mean f SD), y Sex, no. (%) Female Male NA = not applicable. *In some categories, percentages ‘One patient receiving celecoxib
done 10 mg/acetaminophen 1000 mg, and 141 patients receiving placebo. Baseline characteristics, including age, sex, type of surgical procedure, and baseline pain intensity, were comparable between groups (Table I). More celecoxib patients completed the SDAP than did hydrocodone/acetaminophen or placebo patients, and fewer celecoxib patients required rescue medication during the SDAP (P < 0.05). Fifty-five percent of celecoxib patients completed
Celecoxib 200 mg (n = 141)
Hydrocodone 10 mg/ Acetaminophen 1000 mg (n = 136)
Placebo (n = 141)
47.4 + 15.0
43.9 f 15.2
45.2 + 16.0
84 (60) 57 (40)
85 (63) 51 (38)
84 (60) 57 (40)
19 (13)
19 (14) 13 (10)
28 (20)
7 (5)
9 (6) 93 (66)
0 (0) 12 (9) 0 (0) 11 (8) 81 (60)
12 (9) 0 (0) 13 (9) 3 (2) 7 (5) 78 (55)
88 (62) 52 (37) 65.5 f 16.5
98 (72) 38 (28) 62.8 f 16.5
83 (59) 58 (41) 65.5 k 15.3
46.6 + 15.2
44.4 2 16.1
NA
107 (58) 78 (42)
114 (63) 67 (37)
NA NA
1 (1) 11 (8) l(l)
do not total 100 due to rounding error. bad no baseline pain intensity rating entered on the case report form.
233
CLINICAL THERAPEUTICS”
group compared with the hydrocodonel acetaminophen and placebo groups (P < 0.001 at 7 and 8 hours). SPID-8 scores for the active treatments were significantly superior to those for placebo (P < 0.001) (Figure 2).
the SDAP period, compared
with 48% of the hydrocodonelacetaminophen group and 36% of the placebo group. Two patients were withdrawn from the study during the SDAP because of adverse events, and the remaining patients were withdrawn because they received rescue medication. Details of patient disposition are listed in Table II.
Onset of Analgesia Compared with placebo, the active treatments demonstrated superiority on measures of onset of analgesia, including the percentage of patients achieving analgesia and the median time to onset of analgesia. Only 45% of the placebo group achieved analgesia, compared with 64% and 75% of celecoxib patients and hydrocodone/acetaminophen patients, respectively (P < 0.05). The median times to onset of analgesia in the celecoxib and hydrocodonelacetaminophen patients were significantly shorter (35 and 31 minutes,
Pain Intensity DifSerence The celecoxib and hydrocodone/acetaminophen treatments were superior to placebo on most time-specific PID scores (Figure 1). As early as 1 hour postdose, mean PID scores significantly favored celecoxib and hydrocodonelacetaminophen (P s 0.016 at 2-6 hours, except at 1.5 hours in the celecoxib group). At 7 and 8 hours postdose, mean PID scores were significantly superior in the celecoxib Table II. Patient disposition.
Celecoxib 200 mg
Hydrocodone 10 mg/ Acetaminophen 1000 mg
Placebo
P
Single-dose assessment period (SDAP), no. (%) All randomized SDAP patients Withdrawal due to adverse event Patients with ~1 event Patients requiring 2 1 dose of rescue medication Multiple-dose assessment period (MDAP), no. (%)* All randomized MDAP patients Withdrawal due to adverse event Patients with rl event Patients requiring 2 1 dose of rescue medication Lost to follow-up Protocol noncompliance *No patient received placebo during the MDAP.
234
141
136
141
l(1) 16 (11)
l(1) 37 (27)
0 (0) 20 (14)
0.002
62 (44)
70 (51)
90(64)
0.003
185
181
4 (2) 62 (34)
7 (4) 143 (79)
22 (12)
36 (20)
l(1) l(1)
0 (0) 3 (2)
J.S. GIMBEL ET AL.
A Celecoxib 200 mg A Hydrocodone IO mg/acetaminophen 0 Placebo
01
1000 mg
,,,,I,,IIIIIlIII
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
6
Time (h)
Figure
1. Mean pain intensity difference (PID) scores over time during the single-dose assessment period. The visual analog scale ranged from 0 to 3, with 3 representing the worst pain. *P c 0.05, celecoxib and hydrocodone/acetaminophen versus placebo; +P < 0.05, celecoxib versus hydrocodone/acetaminophen and placebo.
-
I_
Celecoxib 200 mg
Hydrocodone 10 mg/ Acetaminophen 1000 mg
Placebo
Figure 2. Summed pain intensity difference scores through 8 hours (SPID-8) during the single-dose assessment period. The visual analog scale ranged from 0 to 3, with 3 representing the worst pain. *P< 0.001, celecoxib and hydrocodone/acetaminophen versus placebo. 235
CLINICAL THERAPEUTICS”
respectively) than in the placebo (>8 hours, P < 0.05).
group
Use of Rescue Medication The median times to first use of rescue medication in the celecoxib and hydrocodone/acetaminophen patients were significantly longer (>8 hours and 7 hours 25 minutes, respectively) than in the placebo group (3 hours 52 minutes; P < 0.05). Fifty-one percent of hydrocodonel acetaminophen patients and 64% of placebo patients required rl dose of rescue medication. In comparison, only 44% of celecoxib patients required rescue medication, despite the fact that more celecoxib patients than hydrocodone/ acetaminophen patients experienced “severe” versus “moderate” baseline pain (P = 0.003 between the 3 groups).
Multiple-Dose
Assessment
Period
Of the 418 patients randomized to the SDAP, 366 continued to the MDAP. During this period, 185 patients were rerandomized to celecoxib (107 women, 78 men), including 129 who had received celecoxib during the SDAP and 56 who had received placebo; 181 patients were rerandomized to hydrocodone/acetaminophen (114 women, 67 men), including 124 who had received hydrocodonelacetaminophen during the SDAP and 57 who had received placebo. There were no significant between-group differences in baseline characteristics, including age and sex (Table I). More celecoxib patients than hydrocodone/acetaminophen patients completed the MDAP and thus the overall study, and fewer celecoxib patients required rescue medication during the
236
(Table II). During this period, 12% of celecoxib patients, compared with 20% of the hydrocodonelacetaminophen patients, required 2 1 dose of rescue medication (P = 0.05). MDAP
Maximum Pain Intensity At the end of each day of the MDAP, the celecoxib group had significantly superior maximum pain intensity scores compared with the hydrocodone/acetaminophen group (P < 0.001, days 2-5) (Figure 3). Number of Daily Doses of Medication On each day of the MDAP, the celecoxib group required fewer doses of study medication than did the hydrocodonej acetaminophen group. Celecoxib patients required an average of 1.9 doses on day 1 and 1.3 doses on day 5, compared with an average of 2.1 and 1.7 doses on the same days in the hydrocodonelacetaminophen group. The difference between groups was significant on days 3 through 5 (P s 0.01). By day 5,41% of patients in the celecoxib group required no analgesic medication, compared with 20% of patients in the hydrocodonelacetaminophen group. American Pain Society Outcome Measures During the MDAP, 88% of celecoxib patients and 93% of hydrocodonel acetaminophen patients reported that they had experienced pain over the preceding 4 days. The celecoxib group had statistically superior scores on each of the 9 measures in the modified APS assessment (P s 0.013) (Figure 4). The composite pain interference score was significantly more favorable in the celecoxib patients (17.8) than in the hydrocodone/acetaminophen patients (24.8; P = 0.001).
J.S. GIMBEL ET AL. 3.0 c! 8 2.5 ul .z? g 2 2.0 & .E $ 1.5 E z ‘3
1.0
5 s a,
0.5
r 0
n Celecoxib 200 mg 0 Hydrocodone 10 mg/ acetaminophen 1000 mg
I l
l
l-7 *
T 1
2
3
4 Day
Figure 3. Mean maximum pain intensity scores on days 2 through 5 during the multipledose assessment period. The rating scale ranged from 0 to 3, with 3 representing severe pain. *P < 0.001, celecoxib versus hydrocodone/acetaminophen.
W Celecoxib 200 mg
Pain right now
0 Hydrocodone 10 mg/ acetaminophen 1000 mg
Worst pain in 4 days Average pain level over 4 days General activity Mood Walking ability Relations with others Sleep Enjoyment
of life I 0
1
I
I
2 3 American
I
I
I
I
I
I
4 5 6 7 6 9 Pain Society Measure
I
10
Figure 4. Scores on American Pain Society measures at day 5. For each measure, the rating scale ranged from 0 to 10, with 10 representing worst pain or worst interference. *P 5 0.013, celecoxib versus hydrocodone/acetaminophen. 237
CLINICAL
Table III. Cumulative adverse events in the single- and multiple-dose randomized patients.*
Adverse Event Patients with ~1 event Nausea Headache Somnolence Vomiting Dizziness Dyspepsia Dry mouth Pruritus Constipation
assessment periods, all
Celecoxib 200 mg (n = 195)
Hydrocodone 10 mg/ Acetaminophen 1000 mg (n = 194)
87 (45) 22 (11) 20 (10) 15 (8) 10 (5) 7 (4) 7 (4) 2 (1) 2 (1) 0 (0)
125 (64) 53 (27) 23 (12) 30 (15) 17 (9) 31 (16) l(1) 5 (3) 6 (3) 6 (3)
*Totals include all patients who took 21 dose of active drug during either the single-dose the multiple-dose assessment period.
Tolerability Adverse events are listed in Table III. During the SDAP, 1 patient from each of the active-treatment groups withdrew due to adverse events. The celecoxib group had the lowest proportion of patients with rl adverse event (1 l%), followed by the placebo group (14%) and the hydrocodone/ acetaminophen group (27%) (P = 0.002 between groups). Across the SDAP and MDAP, patients who had taken ~1 dose of celecoxib had a significantly lower cumulative proportion of adverse events than patients who had taken B 1 dose of hydrocodonelacetaminophen (43% vs 89%; P < 0.001) (Table III). The most frequently reported adverse events in the celecoxib group were nausea (1 l%), headache (lo%), somnolence (8%), vomiting (5%), dizziness (4%), and dyspepsia (4%). With the exception of dyspepsia (P = 0.068), all of these events were observed in a greater proportion of patients in the
238
THERAPEUTICS”
P
0.015 assessment
period or
hydrocodonelacetaminophen group. The most commonly reported adverse events in the hydrocodonelacetaminophen group were nausea (27%; P < O.OOl), somnolence (15%; P = O.OlS), dizziness (16%; P < O.OOl), and constipation (3%; P = 0.015). During the MDAP, 4 patients from the celecoxib group and 7 patients from the hydrocodonelacetaminophen group withdrew because of adverse events. The celecoxib group had a lower proportion of patients with 21 adverse event (33%) compared with the hydrocodone/acetaminophen group (78%; P < 0.001). DISCUSSION The results of these 2 randomized, double-blind, placebo- and active-controlled trials demonstrate the clinical efficacy and tolerability of celecoxib, a COX-2-specific inhibitor, in the treatment of moderate to severe pain after outpatient orthopedic surgery. Onset of analgesia occurred
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within 1 hour of the first dose of celecoxib. Pain relief was sustained through the 5 days of the study, as demonstrated on several measures of efficacy. All single-dose analgesic efficacy variables favored a single dose of celecoxib 200 mg compared with placebo. The median onset of analgesia after a single dose of celecoxib was 35 minutes. The magnitude of analgesic effect over the SDAP was similar to that with hydrocodone/acetaminophen, and the majority of patients completed this S-hour period without requiring another dose of analgesic medication. During the MDAP, measures of efficacy favored celecoxib over hydrocodone/acetaminophen. Over the 5-day period, 80% to 90% of celecoxib patients experienced satisfactory pain relief while taking an average daily dose of 200 mg twice daily without additional rescue medication. These data are consistent with the results of clinical trials in osteoarthritis, in which celecoxib 100 and 200 mg twice daily produced significant relief of acute flare pain from osteoarthritis of the hip*’ and kneel6 within 1 day of the start of treatment and demonstrated continuing efficacy for the remaining 6 days of the assessment. The present study compared the tolerability profile of celecoxib 200 mg taken 3 times a day as needed with that of a similar regimen of a mild opiate combination, hydrocodone 10 mg/acetaminophen 1000 mg. During both assessment periods and cumulatively, celecoxib patients experienced significantly fewer side effects. Cumulatively, twice as many hydrocodone/acetaminophen patients reported 81 adverse effect (eg, nausea, somnolence, dizziness, constipation). Cumulatively, nausea was reported -2.5 times more frequently and dizziness 4 times more frequently in patients treated with hydrocodonelacetaminophen than with
celecoxib. Approximately twice as many hydrocodone/acetaminophen-treated patients reported vomiting and somnolence. Constipation was reported by hydrocodone/ acetaminophen-treated patients but not celecoxib-treated patients. Opioids such as hydrocodone are known to have physiologic properties that alter gastric motility. As a class, they also are known to produce respiratory depression, alteration in mood, physical tolerance, and dose-dependent bradycardia.28 The conditions of the MDAP parallel actual practice after ambulatory orthopedic surgery. Specifically, after undergoing a variety of outpatient procedures, including laminectomy, arthroscopy, and foot surgery, patients were discharged home and allowed to take blinded study medication on an asneeded basis up to 3 times a day. If this was not sufficient to control their pain, they were allowed to take rescue medication, but their participation in the study was discontinued once they did so. A majority of patients required only 2 daily doses of celecoxib 200 mg to manage acute postoperative pain, and the results suggest that the majority achieved satisfactory pain control with few adverse events.
CONCLUSIONS In this study, celecoxib 200 mg was well tolerated taken in single oral doses as needed up to 3 times a day over a 5-day period. The single dose displayed analgesic efficacy in patients with moderate to severe pain after outpatient orthopedic surgery. Taken at a minimum interval of 8 hours over a 5-day period, celecoxib 200 mg displayed analgesic efficacy similar or superior to that of a similar regimen of hydrocodonelacetaminophen. Most patients required only twice-daily doses of
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celecoxib 200 mg to control their acute pain after orthopedic surgery.
ACKNOWLEDGMENTS The following investigators participated in this trial: Steven Belknap, MD, Peoria, Illinois; Nelson G. Botwinick, MD, New York, New York; O.F. Cannon, Jr., MD, Ocala, Florida; Stephen E. Daniels, DO, Austin, Texas; Christopher M. Fallows, DO, Inverness, Florida; Joseph S. Gimbel, MD, Glendale, Arizona; Stephen F. Gordon, MD, Atlanta, Georgia; Marc Z. Hammerman, MD, Hollywood, Florida; Stephen J. Hawes, Jr., MD, Charlotte, North Carolina; W. John Henry III, MD, Greer, South Carolina; Thurman E. Hunt, MD, Newark, New Jersey; Michael Kentor, MD, Pittsburgh, Pennsylvania; Alan J. Kivitz, MD, Altoona, Pennsylvania; Richard M. Konsens, MD, Orlando, Florida; Leonard I. Kraut, MD, Lakewood, New Jersey; Paul Lunseth, MD, Tampa, Florida; Daryl K. MacCarter, MD, Denver, Colorado; Margaret Michalska, MD, Chicago, Illinois; Stephen H. Miller, MD, Las Vegas, Nevada; Robert J. Noveck, MD, PhD, New Orleans, Louisiana; Jon Sanchez, MD, Springfield, Montana; Paul F. Siami, MD, Evansville, Indiana; Randall R. Stoltz, MD, Evansville, Indiana; and B. King Tipton, MD, Fort Myers, Florida.
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Address correspondence to: Joseph S. Gimhel, MD, Medical Director, Arizona Research Center LLC, 2525 W. Greenway Road, Suite 114, Phoenix, AZ 85023. E-mail: [email protected]
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