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Salo et al. CELECOXIB VS IBUPROFEN FOR ACUTE PAIN

A Randomized, Clinical Trial Comparing Oral Celecoxib 200 mg, Celecoxib 400 mg, and Ibuprofen 600 mg for Acute Pain
David F. Salo, MD, PhD, Robert Lavery, MA, MICP, Vikram Varma, MD, Jennifer Goldberg, MS, PA-C, Tara Shapiro, DO, Alan Kenwood, MD Abstract
Objective: Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used to treat pain. The objective of this study was to compare the efcacies of celecoxib and ibuprofen for the treatment of acute pain. The null hypothesis was that no difference between celecoxib and ibuprofen exists. Methods: The study was a prospective, randomized, double-blind, controlled clinical trial. After consent, patients rated their pain on a 100-mm visual analog scale (VAS) and categorical intensity pain scale. Patients were then randomized to receive 200-mg or 400mg celecoxib or 600-mg ibuprofen (all orally). Patients were contacted 5 hours after receiving study medication when a second VAS score was recorded, along with categorical pain intensity, pain relief score, side effects, and number of rescue medications taken. The main outcome measures were change in visual analog pain and categorical pain intensity scores, and pain relief scores, at ve hours. Results: One hundred ten patients were evaluated and 105 were enrolled. Thirty-four received celecoxib 200 mg, 32 received celecoxib 400 mg, and 39 received ibuprofen 600 mg. Ninety-one were available for the ve-hour VAS and 88 for the ve-hour categorical pain intensity and pain relief analysis: The two patients who were unable to read a VAS were excluded, and two enrolled patients withdrew prior to medication. One patient was excluded because his injury was a fracture, and therefore did not meet the inclusion criteria. There was no statistical difference among the treatment groups in age, time from injury to medication, initial VAS score, percent lost to follow-up, or treatment with adjunctive therapy. There was no statistical difference in change of VAS among the groups at ve hours: ibuprofen 600 mg (23.8 mm [95% CI = 31.56 mm to 16.1 mm] [n = 32]), celecoxib 200 mg (16.1 mm [95% CI = 24.3 mm to 7.98 mm] [n = 31]), and celecoxib 400 mg (12.4 mm [95% CI = 23.1 mm to 1.8 mm] [n = 30]) (p = 0.16). There was no signicant difference between the groups, at ve hours, in change of categorical pain intensity (p = 0.11) or pain relief scores (p = 0.059), though the pain relief scale approached signicance favoring ibuprofen. Conclusions: No signicant difference exists among emergency department (ED) patients treated for acute pain, at ve hours, with celecoxib 200 mg, celecoxib 400 mg, or ibuprofen 600 mg, though the power of the study to detect a change was low, 36%. However, the magnitude of pain relief for celecoxib, coupled with the cost of the medication, questions its use in the immediate ED setting. Key words: pain; analgesia; celecoxib; ibuprofen; cost. ACADEMIC EMERGENCY MEDICINE 2003; 10: 2230.

Acute musculoskeletal extremity injuries are common presenting complaints to the emergency department (ED). Initial treatment of such injuries is frequently with nonsteroidal anti-inammatory drugs (NSAIDs), which are one of the most commonly prescribed drugs, despite their potential toxicity.1,2 These agents are effective in the treatment of pain due to injuries of this type, have low nancial cost, and are at low potential for abuse. Since
From the Department of Emergency Medicine, Newark Beth Israel Medical Center (DFS, VV, JG, TS, AK), Newark, NJ; and the Department of Surgery, Division of Trauma, UMDNJ-New Jersey Medical School (RL), Newark, NJ. Received May 7, 2002; revision received August 12, 2002; accepted August 28, 2002. Supported in part by an unrestricted educational grant from Pzer. Address for correspondence and reprints: David Salo, MD, PhD, Department of Emergency Medicine, 201 Lyons Avenue, Newark, NJ 07112. Fax: 973-282-0562; e-mail: ds1122@aol.com.

NSAIDs affect cyclooxygenase-1 (COX-1), however, production of prostaglandins that act in non-pain pathways are also inhibited. Some of the side effects that NSAIDs may cause include abdominal pain, diarrhea, dyspepsia, atulence, and nausea. More serious is that agents that inhibit COX-1 can have a deleterious effect on renal function, platelet aggregation, and the mucosal barrier of the gastrointestinal (GI) tract, leading to avascular necrosis of renal tubules and GI bleeding. Celecoxib was the rst NSAID designed to primarily inhibit COX-2 activity with minimal activation of COX-1. While celecoxib will inhibit COX1, concentrations greater than two orders of magnitude higher than needed to inhibit COX-2 are required (in vitro test systems).3 This selective inhibition of COX-2 may decrease the incidence of side effects caused by agents that inhibit COX-1, making this drug an attractive option for patients

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TABLE 1. Exclusion Criteria
Refusal or inability to give informed consent Pregnancy Treatment with glucocorticoids in past 2 weeks History of gastritis, peptic ulcer disease, gastroesophageal reux disease, ulcerative colitis, or other inammatory bowel disease History of bleeding disorders or hyper/hypo-coagulation defects History of P450 deciency History of acute or chronic hepatic disease History of congestive heart failure History of renal insufciency or failure Use of uconazole Use of lithium Having already taken some form of analgesia, including acetaminophen, nonsteroidal anti-inammatory drugs (NSAIDS), or opioid or nonopioid pain relievers, 12 hours prior to presentation in the emergency department Radiographic diagnosis of fracture or dislocation Known allergy to NSAIDs Know allergy to sulfa medication Known allergies to acetaminophen or codeine Not having a phone or not being available for phone followup at 5 hours Chronic pain More than mild head injuries Chronic back pain Inability to ll and read the visual analog scale (VAS) Prior enrollment in this study Being seen between 5 PM and 5 AM

who are predisposed to GI bleeding disorders. Because of these properties, celecoxib has become one of the most prescribed medications in the United States, and was recently approved by the Food and Drug Administration (FDA) for the treatment of acute pain. A review of the literature, when celecoxib is entered as the search term on PubMed, lists 420 papers published on this medication since it was approved four years ago. While celecoxib is now widely prescribed, and has FDA indications for the treatment of acute pain, to the best of our knowledge, there are currently no studies on the use of celecoxib in the ED setting, and few comparing celecoxib with the medication it would be used in lieu of for ED patientsibuprofen. Our study was conducted to compare the efcacies of celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 600 mg in ED patients with acute pain of musculoskeletal origin.

METHODS
Study Design. This was a randomized, doubleblind clinical trial in a convenience sampling of patients, to compare the efcacies of celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 600 mg (all orally) for the treatment of acute musculoskeletal pain. The null hypothesis was that no difference between celecoxib and ibuprofen exists. The institutional review board of the hospital approved the study. Written prospective informed consent was obtained from all participants. Study Setting and Population. The setting was the adult side of an inner-city hospital ED serving a predominantly African American population (95%). The ED supports an emergency medicine resident program with a combined adult and pediatric volume of 75,000 patients/year. Patients were recruited from August 2000 to November 2001. Study Protocol. Patients underwent initial assessment by the study authors or research associates (medical or dental students) to determine whether they met eligibility criteria for study enrollment, including: age greater than or equal to 18 years and a chief complaint of acute musculoskeletal injury to the extremity for which ibuprofen would normally be given. These injuries included, but were not limited to: contusions, abrasions, lacerations, strains, crush injuries, sprains; related to soft tissue trauma such as direct trauma, twisting, crushing injuries, or overuse syndromes. Table 1 lists the exclusion criteria. Fracture is listed as an exclusion criterion since some physicians might not give ibuprofen to

patients with certain fractures types, especially those causing pain that is more signicant. Since our study protocol was designed to study patients at the ve-hour post-medication time period, we devised a unique visual analog scale (VAS) instrument, in advance, that would allow patients to calculate and report their VAS measurements from home. Subjects who agreed to participate in the study were rst asked to mark their level of pain on a 100-mm VAS designed specically for use by patients. This VAS is a two-page carbonless copy instrument with a 100-mm un-hatched visual analog scale, bounded on the left with least possible pain and on the right with worst possible pain, printed on the top page. The bottom page contains a hatched 100-mm scale, marked numerically in increments of 10 mm. Each 5-mm midpoint is demarcated with a slightly smaller unmarked hatch and individual millimeters are distinguished by yet smaller unmarked hatches. The two pages are joined at the top so scales are perfectly aligned. A mark made on the top scale transfers to the exact same area on the bottom, hatched scale. In keeping with the accepted use of the VAS to record pain intensity, the patient had no knowledge of the numerical score when the top scale was graded. After marking the unhatched scale, the patient was asked to read the numerical value in mm from the bottom

24
hatched scale. Following this, the patient no longer had access to the initial VAS, and the enrolling physician then separately read the scale. Since patients would be self-administering a similar visual analog pain scale at home, a difference in patient reading of more than 2 mm from the enrolling physician was considered inaccurate, and any patient reading his or her scale greater than this difference was excluded from the study. Patients within 2 mm were fully consented, and demographic data were entered on a standardized study form. Patients were also asked at this time to rate their pain on a categorical pain-intensity scale consisting of four rankings (none, mild, moderate, and severe). The VAS was validated for patient use prior to being implemented. For this trial, 95% of patients were able to read their VAS within 2 mm of physician reading, in the ED setting (data not presented). Randomization into study groups was done using a computerized random-numbers table generated by the principal investigator (DFS). Study medications were placed into opaque pill bottles to ensure blinding. The study bottles were sequentially labeled from the random-numbers table and kept secure in an electronically locked medication cabinet, which could be accessed only by password, for the duration of the study. Once the patient was fully enrolled, and prior to receiving medication, the treating physician wrote the order for the study medication into the patients chart. The next sequentially numbered pill bottle was then obtained from the locked medicine cabinet and the patients name and number were recorded on a patient enrollment ow sheet. When presented with study medication, the patient was asked by the enrolling physician to put the contents of the bottle, without looking inside, into his or her mouth. To minimize bias, since the 400-mg celecoxib subjects would be taking two pills (2 celecoxib 200 mg), while both the 600-mg ibuprofen and the 200-mg celecoxib groups would be taking one pill, patients were advised that they would be taking either one or two pills, regardless of medication or dose being given. A cup of water was provided. Study medication could be given at the discretion of the enrolling physician, even if an x-ray was ordered, if there was low index of suspicion for fracture. If an x-ray was being performed because fracture was suspected, the study medication was given only after the x-ray was reviewed by the treating physician and read as negative. If a patient was enrolled and his or her x-ray was read as positive for fracture prior to being administered study medication, the patient was withdrawn from the study. When ready for discharge, the patient was given a vial containing three acetaminophen with

Salo et al. CELECOXIB VS IBUPROFEN FOR ACUTE PAIN

codeine tablets to be used as rescue medication, if needed. The patient was also provided with a second unmarked VAS, similar to the one initially lled out, along with a stamped envelope addressed to the principal investigator. The patient was advised that he or she would ll in the VAS at the time of ve-hour callback. All discharged patients were appropriately treated for their injuries and given follow-up instructions by the treating physician. Patients were also given prescriptions for additional pain medication, at the discretion of the treating physician, dated for the next day so as not to interfere with study or rescue medication and to ensure that additional ibuprofen or celecoxib was not given during the study period. Patients were instructed to return to the ED if they became worse in any way, were given time off of work appropriate for their injuries, and were instructed on follow-up. Five hours after taking the study medication, the patient was contacted by telephone, and was instructed to ll out the second unmarked VAS and to report the number over the telephone. At this time, patients were asked whether, and how many, rescue pills were taken, and when the rst pill was taken. Patients were also asked to rank their pain on the categorical pain intensity scale and on a pain relief scale marked: none, a little, some, a lot, complete. Overall drug tolerability was rated using a ve-point scale (poor, fair, good, very good, excellent). Subjects were additionally asked whether they had experienced any other symptoms or side effects or whether anything unusual had occurred since receiving the study medication. At the end of the callback, patients were requested to mail back the completed ve-hour VAS the following day. Data Analysis. Data were entered into a Microsoft Excel 7.0 (Microsoft, Redmond, WA) database and analyzed using SPSS 7.0 (SPSS Inc, Chicago, IL) and Analyse-It Software (Analyse-It Software Ltd., Leeds, UK). Demographic data were analyzed according to the following variables: age, gender, time from injury to study medication, and use of adjunctive therapy, including Ace wrap, immobilization with sling or posterior splint, or crutches. Response variables across groups included initial visual analog pain scores, change in visual analog pain, change in categorical pain intensity, and categorical pain relief scores. All statistical analysis involved two-tailed tests. Alpha was set as 0.05. Demographic and baseline clinical variables were analyzed with chi-square or Fishers exact test for categorical values and analysis of variance (ANOVA) for continuous variables. VAS pain relief

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was given additional rescue pain medication prior to discharge. However, the patient was not available for ve-hour follow-up data. There was no signicant statistical difference among the treatment groups in age, time from injury to medication, initial VAS score, or use of adjunctive therapy (Table 2). There are data missing for one patient in each group on use of adjunctive therapy. More females than males were enrolled, and this was signicant (p = 0.02). Five-hour VAS data were collected for 91 patients (86.7% of those enrolled). Follow-up for the remaining 14 (13.3%) was not obtained because the patient either did not answer the phone, was not at home, or left an erroneous phone number and did not mail back the ve-hour visual analog pain scale. Eighty-eight patients with ve-hour VAS data were successfully contacted by telephone and 40 patients mailed back their VASs. Three patients who could not be reached at ve hours were among the 40 who mailed back their VASs. Since categorical and pain relief scales were conducted only by telephone, this left 88 patients available for analysis of these scales. Patients lost to follow-up were younger, median age 23.5 vs. 30.0 years (p = 0.03), than those contacted or who sent back their VASs. There was no signicant difference in median time of injury to study medication, initial VAS, or percent lost to follow-up, between groups, for those contacted versus lost to follow-up (Table 2). There was no statistical difference between groups in visual analog pain scales at time 0 or at ve-hour callback, or in mean change of visual analog pain scale at ve hours (Table 3). For ibuprofen 600 mg, the mean decrease in ve-hour visual analog pain scale was 23.8 mm (95% CI = 31.56 mm to 16.1 mm) (n = 32); for celecoxib 200 mg, 16.1 mm (95% CI = 24.3 mm to 7.98 mm) (n = 31); and for celecoxib 400 mg, 12.4 mm (95% CI = 23.1 mm to 1.8 mm) (n = 30) (p = 0.17). There was no signicant difference in change in ve-hour categorical pain intensity (p = 0.11) or pain relief scores (p = 0.059), though the pain relief scores approached signicance in favor of ibuprofen 600 mg (Table 3). In this study, with a total sample size across three groups of 91, a one-way ANOVA will have a 36% power to detect a difference of 13 mm at an alpha of 0.05, assuming a common standard deviation of 22.8 (the SD of the study). Five patients used rescue medication, one in the ibuprofen 600-mg group and two each in the celecoxib 200-mg and celecoxib 400-mg groups. The patient in the ibuprofen 600-mg group (mentioned above) was given rescue medication for a fracture prior to discharge from the ED, was not available for ve-hour data, and did not mail back the ve-

was calculated by subtracting the interval pain scores from the baseline pain score for each group. This score, and the initial visual analog pain scale, among groups, was analyzed using ANOVA. We anticipated analyzing ve-hour data with and without adjustment for patients who received rescue medication. Categorical pain intensity, change in categorical pain intensity, categorical pain relief, and drug tolerability were analyzed using chisquare or Fishers exact test. Since patients were to mark, read, and report by phone, from home, their ve-hour VAS results, and because the VAS instrument had been validated for patient use by patients in the ED setting, but not at home, Pearsons productmoment correlation was used to analyze physicianpatient readings of all ve-hour VASs returned by mail. Since we expected that a portion of patients would not mail back their VAS scores, we determined that patient readings would be used for all nal calculations, even if they were more than 2 mm different from physician readings. Sample size determination. Assuming a standard deviation of 20 mm and a clinical signicant change in VAS (delta) of 13 mm (based on work by Todd et al.4), the program we used (accessed at http: // www .stat. uiowa. edu / rlenth / Power / index. html) determined a power of 0.80, at the 95% condence level, using ANOVA, with 48 subjects per group. Post-hoc calculations were performed using nQuery Advisor 1.0 (Statistical Solutions, Crosses Green, Cork, Ireland).

RESULTS
One hundred ten patients were evaluated and 105 were enrolled, were randomized, and received study medication. There were 39 in the ibuprofen 600-mg group, 34 in the celecoxib 200-mg group, and 32 in the celecoxib 400-mg group. Two patients unable to accurately read their initial VAS pain scales were excluded, two enrolled patients withdrew prior to receipt of study medication, and one patient who was enrolled but did not receive study medication was excluded secondary to fracture (none of these patients were randomized into groups, Fig. 1). Sixty-ve women and 40 men were enrolled (p-value = 0.02). Ninety-seven (92%) of the patients were African American, three (2.8%) were white, two (1.9%) were Hispanic, two (1.9%) were Middle Eastern, and one (0.9%) was Native American. Seventy-four patients (70.4%) received an x-ray, of which all were negative except one in the ibuprofen 600-mg group. This patient was administered study medication, and

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Salo et al. CELECOXIB VS IBUPROFEN FOR ACUTE PAIN

Figure 1. Flow diagram of subject progress through the phases of the study. VAS = visual analog scale.

hour VAS. The two patients in the celecoxib 200mg group took rescue medication within 15 minutes of callback, one 15 minutes prior and the second at the time of callback, and because of this both were included in the ve-hour analysis. In the celecoxib 400-mg group, one patient took rescue medication at the time of ve-hour callback (included in analysis), while the second patient took rescue medication 4.5 hours prior to callback. The second patient had an increase in 5 mm on the VAS at ve-hour callback and was included in the analysis. Excluding this patient would not substantially change the data for this group.

Five patients in the celecoxib 400-mg group and three in the celecoxib 200-mg group reported minor side effects, including drowsiness, dizziness, funny taste, dry mouth, and blurry vision, with no side effects related to the GI tract. Seven patients in the ibuprofen 600-mg group reported side effects, including drowsiness, dizziness, and minor GI symptoms such as nausea, gas, and stomach cramping. No other side effects, complaints, or complications were reported. Pearsons productmoment correlation for the 40 available VAS scales returned by mail showed excellent physicianpatient correlation (r = 0.99).

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TABLE 2. Demographics of the Study Groups

Ibuprofen 600 mg (n = 39) Gender Females Males Time from injury to study medication median Agemedian Initial VAS* scoremean (95% CI) 23 16 20 hr Celecoxib 200 mg (n = 34) 27 7 16 hr Celecoxib 400 mg (n = 32) 15 17 25 hr p-value

p = 0.02 p = 0.21

28 yr 55.7 mm (49.2, 62.1) 32 (82%)

28 yr 57.1 mm (49.9, 64.2) 30 (88%)

33 yr 50.8 mm (42.7, 59.1) 29 (91%)

p = 0.51

Patients available for 5-hour callback Adjunctive therapy Ace wrap Splint/sling Crutches Follow-up Median age Median time from injury to medication Mean initial VAS score (95% CI)

p = 0.54

12/38 (32%) 15/38 (39%) 16/38 (42%) Lost to Follow-up (n = 14) 23.5 yr 25.8 hr 54.9 mm (43.4, 66.5)

8/33 (23%) 10/33 (30%) 15/33 (45%)

8/31 (26%) 9/31 (29%) 13/31 (42%)

p = 0.76 p = 0.60 p = 0.95 p-value p = 0.03 p = 0.37

Five-hour VAS Follow-up Available (n = 91) 30.0 yr 18.3 hr 54.2 mm (50.2, 59.1)

*VAS = visual analog scale.

TABLE 3. Timed Visual Analog Scale (VAS) Scores, Change in 5-hour Categorical Pain Intensity Scores, and 5-hour Pain Relief Scores
Time 0 VAS, 5-hour VAS, and Change in VAS at 5-hour Callbackmm (95% CI) Time 0 VAS 5-hour VAS Change in VAS at 5 hours Change in 5-hour Categorical Pain Intensity above or below Initial Score 1 (increase) 0 (no change) 1 (decrease) 2 (decrease) 5-hour Pain Relief None A little Some A lot Complete Ibuprofen 600 mg (n = 32) 55.8 mm (48.9, 62.7) 31.9 mm (23.3, 40.6) 23.9 mm (31.6, 16.2) Ibuprofen 600 mg (n = 32) 1 9 15 7 (3%) (28%) (47%) (22%) Celecoxib 200 mg (n = 30) 58.6 mm (50.7, 66.4) 42.4 mm (32.4, 52.4) 16.2 mm (24.4, 8.0) Celecoxib 200 mg (n = 28) 2 14 9 3 (7%) (50%) (32%) (11%) Celecoxib 400 mg (n = 29) 49.3 mm (40.5, 58.1) 36.8 mm (26.4, 47.3) 12.5 mm (23.1, 1.8) Celecoxib 400 mg (n = 28) 4 10 11 3 (14%) (36%) (39%) (11%) p-value p = 0.23 p = 0.29 p = 0.17

p-value

p = 0.11 p-value

Ibuprofen 600 mg (n = 32) 0 8 10 8 6 (0%) (25%) (31%) (25%) (19%)

Celecoxib 200 mg (n = 28) 2 9 9 6 2 (7%) (32%) (32%) (22%) (7%)

Celecoxib 400 mg (n = 28) 5 10 1 7 5 (18%) (36%) (3%) (25%) (18%)

p = 0.059

Pearsons r in the study that validated patients ability to read a VAS was also 0.99. There were two patients in this study who met all eligibility criteria when enrolled, including the ability to read the VAS within 2 mm of physician readings, who subsequently read their ve-hour VAS at home more

than 2 mm from physician readings. One patient in the ibuprofen 600-mg group reported a ve-hour score of 20 mm, while the physician reading was 26 mm. One patient in the celecoxib 400-mg group reported 62 mm at ve hours, while the physician reading was 65 mm.

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Salo et al. CELECOXIB VS IBUPROFEN FOR ACUTE PAIN

DISCUSSION
Pain from musculoskeletal injury is a common complaint, accounting for more than 36 million annualized injury-related visits to the ED, for all ages, in 19971998.5 NSAIDs, particularly ibuprofen, are frequently used to treat pain of this type and work by inhibiting prostaglandin synthesis through the enzyme cyclooxygenase (COX). However, two isoforms of COX are active in the body, COX-1 and COX-2. COX-1 is involved in the production of housekeeping prostaglandins, which help maintain physiologic function, by 1) working to regulate and maintain the mucosal barrier of the GI tract, 2) affecting platelet aggregation through regulation of thromboxane A2, and 3) helping to regulate renal blood ow.6 Primarily COX-2, but not COX-1, is upregulated by the action of cytokines and endotoxins in inamed or injured tissues, producing pro-inammatory prostaglandins, important mediators in the pain.7 Ibuprofen and other NSAIDs are known to inhibit both COX-1 and COX-2 activity. A result of this action is to prevent the formation of pro-inammatory prostaglandins. Though NSAIDS are generally safe and effective, there are subgroups of patients who should not take medications such as ibuprofen, which inhibit both the COX-1 and COX2 enzymes. These include patients with a history of peptic ulcer, gastritis or other underlying GI disease, renal disease, advanced age, and other comorbid conditions predisposing to the harmful effects of NSAIDs. Historically, opioids have frequently been substituted for patients who cannot take NSAIDs. While these medications can be very effective in pain control, care must be taken when given to patients with a history of drug or alcohol abuse, those with head injury, elders, or those operating machinery or motor vehicles. These concerns led to the development of COX-2 selective inhibitors. Since FDA approval in 1999, celecoxib and a second COX-2 selective inhibitor, rofecoxib, have become widely used in the treatment of chronic pain. On initial FDA review, rofecoxib was granted approval for the treatment of acute pain, while celecoxib, which was originally approved to treat chronic inammation, was recently granted similar status. Our study compared celecoxib and ibuprofen for the treatment of acute pain in the ED setting. Since this was a blinded study, patients with contraindications to ibuprofen were excluded. Phase II osteoarthritis and rheumatoid arthritis (RA) trials established the minimum effective dose of celecoxib for these conditions, 100 to 400 mg/day for osteoarthritis and 200 to 800 mg/day for RA.6 Since few

data exist on the optimal dose of celecoxib for acute pain, two doses, 200 mg and 400 mg, were used in this study. While our data showed no difference between either strength of celecoxib and ibuprofen, the numbers of patients enrolled were low and post-hoc analysis determined that the ability to detect a true difference between groups was 36%. Despite this, it is interesting to note that the levels of pain relief among the two doses of celecoxib were similar and, though not signicant, consistently lower than that delivered by ibuprofen. Celecoxib therefore may not be an ideal medication for treating patients in acute pain from musculoskeletal injuries in the immediate ED setting. Based on work by Todd et al., the accepted minimum clinically signicant difference for pain relief (MCSD) on a 100-mm VAS is 13 mm.4 Accordingly, celecoxib in both doses decreased pain, but just by the MCSD. On the pain relief scale, the data approached signicance in favor of ibuprofen. While some patients obtained excellent pain relief with celecoxib, both celecoxib groups contained patients who reported no change, or pain increase, in the rst ve hours on this medication. Table 3, the change in ve-hour categorical pain intensity, shows that 7% in the celecoxib 200-mg group, and 14% in the celecoxib 400-mg group, reported an increase in pain of one level on the Likert scale, compared with 3% for the ibuprofen group. On the vehour pain relief score, 7% of patients taking celecoxib 200 mg, and 18% of those taking celecoxib 400 mg, reported no pain relief, compared with 0 patients who took ibuprofen 600 mg. Analysis of the data showed no difference in median age, median time of injury to study medication, initial VAS score, percent of patients available for ve-hour data, or treatment with additional modalities, such as splints, slings, or crutches, to account for this. More females than males were enrolled; the numbers enrolled by group were not equal and this was statistically signicant (p = 0.02). However, this may simply reect the demographics of our ED, where approximately 6065% of patients are female. In addition, the celecoxib 200-mg group had 20% male patients, the celecoxib 400-mg group had 53% males, and the ibuprofen 600-mg group had 41% males. If differences in gender accounted for the greater number of patients reporting no or little pain relief in the celecoxib groups, then one celecoxib group should have performed slightly better than ibuprofen and the other should have performed worse. The two groups, however, were similar. The loss to follow-up of 14 (13.3%) patients could also have inuenced the results. Analysis of patients lost to follow-up showed

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celecoxib 200-mg and ibuprofen 600-mg groups received one pill each. Attempts were made to limit the effect of patients in different groups receiving different numbers of pills by advising all patients they would receive either one or two pills, regardless of randomization group. Still, patients who received two pills may have perceived they were receiving a higher dose of a medication. Since those patients who actually received two pills, the celecoxib 400-mg group, faired no better than the celecoxib 200-mg group, this did not seem to inuence the results in favor of this dose of celecoxib. Another limitation was that data were collected for one time point, ve hours post-study medication ingestion. This time point was picked, however, to maximize the pain relief expected from celecoxib. Although dental studies had shown relief of pain within 3045 minutes for celecoxib when compared with placebo,10 few data existed to show whether a loading dose was needed to obtain maximum relief.3 Since celecoxib is dosed every 12 hours (or every 24 hours for higher doses or certain conditions) and ibuprofen every six to eight hours, we expected a ve-hour data point to maximize the pain relief effects of celecoxib. Our study used a dose of 600 mg for ibuprofen, since this is the dose commonly used in our ED. Certainly, an 800-mg dose of ibuprofen may have shown a signicant or greater increase in the effectiveness of this medication when compared with either dose of celecoxib. Other data have shown ibuprofen to be equally efcacious in the treatment of acute pain in patients with ankle sprains.12,13 However, the data points for that study were four and ten days post-treatment. Most patients, and their treating emergency physicians, look toward a much shorter time period for relief of pain, whether from musculoskeletal injury or not. Certainly, celecoxib could still be used after the initial treatment period in the ED, if its costbenet ratio supports it. However, this would necessitate starting the patient on celecoxib in the ED, while providing a period of treatment with another medication, such as an opioid, until the celecoxib took full effect. This would also be contingent on studies showing that patients who initially report no pain relief or increase in pain, obtain pain relief at later times on celecoxib. Conversely, because we had only one time point for evaluation, patients in our celecoxib groups may have had greater pain relief in the rst four to ve hours, with the effects of the medication wearing off at the time of the ve-hour callback. When this study was designed, we had no reason to believe this would be the case, and dosing for celecoxib continues to be once or twice a day. However,

that those patients lost were younger than those with follow-up, 23.5 vs. 30 years (signicant to p = 0.03). Because our ED serves an inner-city population, we had expected up to 20% or more loss to follow-up. Of note, one recent study comparing celecoxib with rofecoxib and acetaminophen for osteoarthritis of the knee also had 79% of patients completing the study.8 The visual analog pain scale designed for patients to use, with results that could be read over the phone, certainly helped minimize data loss. The fact that only 40 (38%) patients mailed back their VASs, and the fact that analysis of those scores reveals excellent physicianpatient correlation (r = 0.99), yet data loss was kept to 13.3%, supports the continued use of this scale for data collection. We originally designed this study with both four-hour categorical and numerical VAS scores in the event that some patients, once discharged from the ED, would no longer be able to accurately read the VAS. Though correlation remained excellent, two of the 40 patients who returned the VAS by mail, who initially read the VAS in the ED within 2 mm of the enrolling physician, read their VAS at home more than 2 mm from physician readings. While these differences are low and do not measurably alter the data, we do not know why the patient readings deviated from physician readings by more than 2 mm. Our results are consistent with other recent studies.810 In one study, rofecoxib scored similar to ibuprofen in overall analgesic effect, with both medications scoring 30% better than celecoxib.9 Matheson and Figgitt, in a review of patients with acute or chronic pain, reported that rofecoxib provides efcacy similar to ibuprofen, but better than celecoxib.10 This was attributed to rofecoxibs greater selectivity for COX-2 than celecoxib, while Matheson and Figgit noted that celecoxib may have been used at subtherapeutic doses in some studies. We studied the standard 200-mg single dose and a higher 400-mg dose. Since a 30-day supply of celecoxib 200 mg (one twice a day) costs approximately $70, compared with $30 for an ibuprofen prescription of 600 mg three times a day,11 celecoxib would be attractive for ED patients with contraindications to ibuprofen if it provided more than just the MCSD for pain relief for all patients, or at least similar proportions of patients, when compared with ibuprofen.

LIMITATIONS
In addition to the low numbers of enrolled patients and power, there are several other limitations to this study. First, some patients received two pills (celecoxib 400-mg group), while the patients in the

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data to support a shortened time efcacy for celecoxib exist. Malmstrom et al., when comparing celecoxib with rofecoxib in patients with dental pain, found a longer time to pain relief with celecoxib (60 minutes vs. 30 minutes) and a shorter duration of effect (5.1 hours vs. 24 hours).10 In this case, celecoxib should be dosed every six hours, doubling the cost of the drug to $140 for a onemonth supply. A nal limitation of our study is the homogeneous nature of our patient population, where 92% of subjects were African American. Racial differences in response to medications are recognized, and racial differences in drug disposition for celecoxib have been reported.14,15 Celecoxib was found by a meta-analysis of pharmacokinetic studies to have a 40% higher AUC (area under the curve) and 11% lower CL/F (serum clearance) in African American patients compared with white patients. It was suggested that very high concentrations of celecoxib in several subjects in this meta-analysis might be due to deciency of CYP2C9, the enzyme that degrades celecoxib. While one would not normally expect a higher AUC and lower serum clearance of a medication to cause a decrease in a medications efcacy, the clinical signicance of these data is unknown. Additional yet undiscovered differences in drug prole based on racial lines other than CYP2C9 might exist. Multicenter studies comparing a more diverse racial prole, with multiple time points, and including other or newer COX-2 inhibitors, could help determine the best COX-2 inhibitor, and dose, for patients in the ED setting.

Salo et al. CELECOXIB VS IBUPROFEN FOR ACUTE PAIN

warranted to determine the role of this medication in the ED setting.

The authors thank the Emergency Department nurses, staff, attendings, and residents; Frank Wieczorek, MS, Assistant Director of Pharmacy, Cheryl Krempa, RPh, MBA, Director of Pharmacy, and Claudetta Bazemore of the Department of Pharmacy, Newark Beth Israel Medical Center Hospital; the following Research Associates: Jon Horstein, Herald Ostovar, Aditya Malinkar, Birju Patel, Marinelle Platon, Shankar Santhanam, and Kirti Tandon, MPH; Steven Bernstein, MD; and John C. Pezzullo, Department of Pharmacology and Biostatistics at Georgetown University.

References
1. 2. 3. Hawkey CJ. COX-2 inhibitors. Lancet. 1999; 353:30714. Lane NE. Pain management in osteoarthritis: the role of COX-2 inhibitors. J Rheumatol. 1997; 24(suppl 49):204. Simon LS, Lanza FL, Lipsky PE, et al. Preliminary study of the safety and efcacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efcacy and safety in two placebocontrolled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum. 1998; 41:1591602. Todd KH, Funk KG, Funk JP, Bonacci R. Clinical signicance of reported changes in pain severity. Ann Emerg Med. 1996; 27:4859. CDC National Center for Disease Statistics. Available at: http://www.cdc.gov/nchs/products/pubs/pubd/hus/ tables/2000/00hus084.pdf. Accessed Feb 2002. Lefkowith JB. Cyclooxygnease-2 specicity and its clinical implications. Am J Med. 1999; 106(suppl 5b):43s50s. Smith CJ, Zhang Y, Koboldt CM, et al. Pharmacological analysis of cyclooxygenase-1 in inammation. Proc Natl Acad Sci U S A. 1998; 95:133138. Geba GP, Weaver AL, Polis AB, Dixon ME, Schnitzer TJ. Efcacy of refecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee: a randomized trial. JAMA. 2002; 287:6471. Malmstrom K, Daniels S, Kotey P, Seidenbery BC, Desjardins PJ. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther. 2001; 21:165363. Matheson AJ, Figgitt DP. Rofecoxib: a review of its use in the management of osteoarthritis, acute pain, and rheumatoid arthritis. Drugs. 2001; 61:83365. ePocratesRx Clinical Drug Database. Available at: http://www.epocrates.com. Accessed Mar 2002. Petrella R, Ekman E, Levy S, Fort J. Comparison of efcacy between celecoxib and naproxen or ibuprofen in the treatment of ankle sprain [abstract 71]. Ann Emerg Med. 2001; 38:S22. Ekman E, Levy S, McDonald S, Fort J. Efcacy of celecoxib compared with ibuprofen in the treatment of ankle sprain [abstract 72]. Ann Emerg Med. 2001; 38:S22. Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Ann Rev Pharmacol Toxicol. 2001; 41:81550. Davies NM, Gudde TW, de Leeuw MA. Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert Opin Pharmacother. 2001; 2:13952.

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CONCLUSIONS
Celecoxib, a COX-2 selective inhibitor, was compared with ibuprofen for the treatment of acute musculoskeletal injuries. In both doses studied, celecoxib was not statistically different from ibuprofen with regard to pain relief on the 100-mm VAS, the categorical pain intensity scale, or the pain relief scale. However, the power of this study to detect a true difference was 36%. In addition, celecoxib consistently provided relief at the lower end of all scales and on one, the pain relief scale, approached signicance in favor of ibuprofen. Because of celecoxibs cost, we cannot currently recommend its use in the immediate ED setting for the treatment of acute pain. Further studies are

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