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J Am Dent Assoc, Vol 133, No 5, 611-621.
© 2002 American Dental Association
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CLINICAL PHARMACOLOGY

JADA Continuing Education

The analgesic efficacy of valdecoxib vs. oxycodone/acetaminophen after oral surgery



STEPHEN E. DANIELS, D.O., PAUL J. DESJARDINS, D.M.D., Ph.D., SHEELA TALWALKER, Ph.D., DAVID P. RECKER, M.D. and KENNETH M. VERBURG, Ph.D.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background. The authors conducted two studies to compare the analgesic efficacy and safety of the cyclooxygenase, or COX, -2–specific inhibitor, valdecoxib, with oxycodone/acetaminophen in patients who have undergone oral surgery.

Methods. In total, 205 eligible subjects in Study A and 201 in Study B were randomized to receive a single oral dose of valdecoxib (20 or 40 milligrams), a combination of oxycodone 10 mg/acetaminophen 1,000 mg or placebo. Eligible subjects experienced moderate-to-severe pain within six hours of surgery during which two or more impacted third molars were extracted. Analgesic efficacy was assessed over 24 hours or until the patient required rescue analgesia.

Results. In both studies, subjects receiving either dose of valdecoxib experienced a rapid onset of analgesia and (among those who received valdecoxib 40 mg) a level of pain relief comparable with that of those who received oxycodone/acetaminophen. Both valdecoxib doses had a significantly longer duration of analgesic effect than did oxycodone/acetaminophen. Pooled safety data demonstrated that each valdecoxib dose had a tolerability profile superior to that of oxycodone/acetaminophen and similar to that of placebo.

Conclusions. Orally administered valdecoxib is as rapidly acting and effective as oxycodone/acetaminophen, and it has a superior duration of analgesic effect in patients after oral surgery. Valdecoxib has a tolerability profile superior to that of oxycodone/acetaminophen.

Clinical Implications. The current standard of care for alleviating acute pain after oral surgery has rested largely on conventional nonsteroidal anti-inflammatory drugs or opioid/analgesic combination products. The studies reported here suggest that the COX-2–specific inhibitor valdecoxib offers an efficacious and safe alternative to other analgesics used to treat pain after oral surgery.

High levels of cyclooxygenase, or COX, -2 are expressed at sites of tissue inflammation, leading to the synthesis of prostaglandins that mediate pain and inflammation.1–3 The likely mechanism of the analgesic and anti-inflammatory actions of nonsteroidal anti-inflammatory drugs, or NSAIDs, is the blockade of prostaglandin synthesis through inhibition of COX. It now is known that there are at least two forms of the COX enzyme and that the expression of COX-2 isoform is induced at sites of tissue inflammation, leading to the synthesis of prostaglandins that mediate pain and inflammation.1–3

The studies reported here suggest that valdecoxib offers an efficacious and safe alternative to treating pain after oral surgery.

Unlike conventional NSAIDs, which inhibit both COX isoforms,4 the COX-2–specific inhibitors inhibit prostaglandin production by COX-2 but have no inhibitory effect on COX-1 at therapeutic doses.5–7 COX-2–specific inhibitors have been shown to be effective in treating the pain and inflammation associated with chronic and acute conditions, such as arthritis and dental pain after surgery.8–10 Furthermore, treatment with COX-2–specific inhibitors is associated with a lower incidence of serious upper gastrointestinal, or GI, and platelet-related adverse events that are characteristic of conventional NSAID therapy.2,4,11 These GI and platelet-related adverse events have been shown to be attributed to COX-1 inhibition.6,11–13

Valdecoxib is a potent and highly selective inhibitor for COX-2, as evidenced by the approximate 28,000-fold difference in the half-maximal concentrations for inhibition, or IC50, of COX-1 (IC50 = 140 micromolars) and COX-2 (IC50 = 0.005 µmol/L) in vitro.14 At a supratherapeutic dose of 40 milligrams twice per day, valdecoxib does not inhibit COX-1, as shown by lack of effect on platelet aggregation.15 Furthermore, valdecoxib is rapidly absorbed, achieving maximal plasma concentrations in approximately three hours (Tmax). 15

Although many opioids and opioid/acetaminophen combinations are effective analgesics, they are relatively short-acting and must be administered every four to six hours. Concerns also exist about the potential for both neuropsychological impairment and drug addiction with these agents, especially in patients who have chronic nonmalignant pain (such as chronic back pain).16 Furthermore, opioid treatment is associated with postoperative side effects such as drowsiness, constipation, nausea, vomiting, circulatory effects and respiratory depression.16–19 The combination of oxycodone and acetaminophen has been shown to be more effective than ibuprofen in treating pain after abdominal gynecologic surgery.20 However, this treatment is associated with an increased incidence of adverse events compared with conventional NSAIDs.20

We conducted the two studies reported here to examine the efficacy of the COX-2–specific inhibitor, valdecoxib, in treating acute pain after oral surgery. We compared the analgesic efficacy and safety of single oral doses of valdecoxib 20 mg and 40 mg with a single oral dose of oxycodone 10 mg/acetaminophen 1,000 mg and with placebo in subjects after oral surgery. The postoperative oral surgery model has been validated for the evaluation of analgesic therapies in previous studies.8,21


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Subjects. The study population for both Study A and Study B included male and female subjects 18 years of age or older who were in good health as determined by medical history and physical examination. We recruited subjects from Central Texas Oral and Maxillofacial Surgery in San Marcos, Texas, and Central Texas Oral Surgery Associates in Austin, Texas. All eligible subjects had undergone surgical extraction of two or more impacted third molars requiring bone removal (one tooth was required to be mandibular) and were experiencing moderate-to-severe postsurgical pain, on a categorical scale, within six hours of surgery. Their pain intensity, or PI, was ≥ 50 millimeters on a 100-mm visual analog scale, or VAS, on which 0 = no pain and 100 = most severe pain. The two studies were conducted in accordance with the World Medical Association’s Declaration of Helsinki.22 All subjects provided written informed consent during the pretreatment screening period before any study procedures were performed.

We excluded from the study any patients who were at that time experiencing a significant GI complaint or had a history of upper-GI ulcer within the previous six months; had nasal polyps; had bronchospasm or angioedema induced by NSAIDs; or had known hypersensitivity to analgesics or cyclooxygenase inhibitors. We also excluded patients who had used tricyclic antidepressants, sedatives, analgesics (including conventional NSAIDs), antihistamines or corticosteroids within the previous 24 hours or who had received acetaminophen within 12 hours before receiving the study medication.

Study design. Each study was a single-center, double-blind, double-dummy, placebo-controlled trial, conducted at the Scirex Clinical Research Centers in San Marcos, Texas (Study A), and Austin, Texas (Study B). We designed them to compare the analgesic efficacy and safety of single oral doses of valdecoxib 20 mg or 40 mg with oxycodone 10 mg/acetaminophen 1,000 mg or placebo in treating patients after they had undergone oral surgery.

We calculated the sample size using the pain intensity difference, or PID, efficacy variable and comparing each valdecoxib dose against placebo. A sample size of 50 subjects per treatment group was required to enable us to detect a difference in the PID score of 0.43 at 45 minutes, with at least 80 percent power and a type I error of .025 (two-sided test adjusted for multiple comparisons). The estimate of variability (standard deviation) we used for sample size calculations in the PID scores at 45 minutes was 0.66.

Each subject received a local anesthetic (2 percent xylocaine with epinephrine 1:100,000) 15 minutes before undergoing surgery. Nitrous oxide–oxygen conscious sedation also was available, if required. After undergoing oral surgery, eligible subjects received study medication according to a previously prepared randomization schedule stratified by pain severity (moderate vs. severe). Subjects, with the assistance of research nurses, assessed their levels of analgesia over a 24-hour treatment period using standard measures of analgesic efficacy (described in the Efficacy Assessments section below). Rescue medication—including acetaminophen 1,000 mg, hydrocodone 5 mg/acetaminophen 500 mg, and hydrocodone 7.5 mg/acetaminophen 500 mg—could be requested by the subject at any time and was administered in accordance with the standard practices at each clinical research center. Both sites followed the same practice with regard to rescue medication: providing it on a subject’s request for additional medication. They used no other criteria. Since all pain assessments had been completed before administration of rescue analgesia, the choice of rescue medication had no bearing on the interpretation of the pain data.

Efficacy assessments. At the time of study medication administration, a two-stopwatch technique was used to measure time to onset of analgesia. This involved study personnel’s starting two stopwatches for each patient. Subjects were instructed to stop the first stopwatch when they first experienced perceptible pain relief, or PR (that is, when they began to feel any pain-relieving effect of the drug). The second stopwatch was stopped when they first experienced meaningful PR (that is, when they began to feel their PR was meaningful). The time to onset of analgesia was defined as the time to perceptible PR if the patient went on to experience meaningful PR within 24 hours of receiving the study medication. Subjects measured their PI and PR at baseline and at one-quarter, one-half, three-quarters, one, one and one-half, two, three, four, five, six, seven, eight, 10, 12, 16 and 24 hours after the administration of study medication and just before the administration of rescue medication, if it was required.

Subjects assessed PI on a four-point categorical scale: none = 0, mild = 1, moderate = 2 or severe = 3. Subjects also recorded their PI on a VAS by placing a vertical mark on a 100-mm line to indicate the magnitude of their pain. Subjects indicated their level of PR according to a five-point categorical scale: none = 0, a little = 1, some = 2, a lot = 3 or complete = 4.

If the investigator/clinician administered rescue medication, the research nurse recorded the time to rescue (time elapsed from administration of study drug to rescue medication). At the end of the 24-hour treatment period or just before taking rescue medication, all subjects completed global evaluations of study medication on a four-point categorical scale: poor = 1, fair = 2, good = 3 or excellent = 4.

Safety assessments. We evaluated general clinical safety by the number and frequency of adverse events during the 24-hour treatment period and up to the posttreatment visit five to nine days after the end of the treatment. In addition, we evaluated changes in vital signs, physical examination findings or clinical laboratory values from baseline to the posttreatment visit (which took place five to nine days postdose).

Statistical analysis. We compared baseline characteristics across treatment groups using an analysis of variance, or ANOVA, with treatment as a factor, the Fisher exact test (for race) or Pearson’s {chi}2 square test (for sex, surgical trauma rating, PI categorical score).

We performed all efficacy analyses on a modified intent-to-treat cohort, comprising all randomized subjects who received study medication but did not receive rescue analgesia or withdraw from the study before the one-hour pain assessment; did not have a protocol violation; or did not miss two consecutive pain assessments in the first two hours. All randomized subjects who received at least one dose of study medication were included in the analysis of safety. We used the last-observation-carried-forward approach in the efficacy analyses to account for missing data due to subjects’ taking rescue medication or withdrawing from the study.

We calculated median time to onset of analgesia and to use of rescue medication using the method described by Miller23 and estimated the associated 95 percent confidence intervals according to the method of Simon and Lee.24 We carried out overall and between-group treatment comparisons using the log-rank test and the pairwise log-rank test (Fisher’s least significant difference method), respectively. For each assessment, we calculated the time-specific PID (categorical scale) by subtracting the categorical PI score from the baseline PI score. The time-interval–weighted summed PID, or SPID, was determined by combining the time-weighted PID scores up to the six-, eight-, 10-, 12-, 16- and 24-hour assessments. We calculated peak PID, or PPID, defined as the highest PID score throughout the 24-hour evaluation period. We analyzed time-specific PID, SPID and PPID and the patient’s global evaluation by analysis of covariance, or ANCOVA, with type of treatment as a factor and baseline PI as a covariate. Using ANOVA, we analyzed time-specific PR with type of treatment as a factor. Using ANCOVA, we calculated and analyzed peak pain relief, or peak PR, defined as the highest PR score throughout the 24-hour evaluation period, with type of treatment as a factor and baseline PI as a covariate. We derived time-specific total pain relief, or TOTPAR, by summing the PR scores through the first six, eight, 10, 12 and 24 hours. We then analyzed TOTPAR using ANOVA with type of treatment as a factor. We pooled safety data from the two studies and analyzed between-treatment differences in the incidence of adverse events using the Fisher exact test.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Subjects: Study A. A total of 205 subjects were randomized to receive treatment. Overall, the treatment groups had similar demographics with no significant differences in mean age, weight, race or male:female ratio (Table 1Go). In addition, similar proportions of subjects in each treatment group experienced moderate or severe pain or surgical trauma (Table 1Go).


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  		TABLE 1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS: SUBJECTS IN STUDY A.

 
Of the 205 subjects randomized to receive study treatment, 52 received treatment with placebo, while 51, 52 and 50 received oxycodone/acetaminophen or valdecoxib 20 or 40 mg, respectively. Of these subjects, 97 completed the study without need for rescue analgesia, whereas 108 (44 who received placebo, 28 who received oxycodone/acetaminophen, 24 who received valdecoxib 20 mg and 12 who received valdecoxib 40 mg) received rescue analgesia. As none of the subjects required rescue medication in the first hour, the cohort for all efficacy analyses included 205 subjects.

Subjects: Study B. In total, 201 eligible subjects were randomized to receive study medication. There were no significant differences in baseline characteristics such as age, weight or sex, and each treatment group had similar proportions of subjects experiencing moderate-to-severe pain or surgical trauma (Table 2Go).


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  		TABLE 2 DEMOGRAPHICS AND BASELINE CHARACTERISTICS: SUBJECTS IN STUDY B.

 
The time elapsing between the end of surgery and the first administration of study medication and the mean number of teeth extracted per treatment group were similar. However, the proportion of subjects who had a complete bony impaction was significantly different (P = .049). Complete bony impaction was observed in 38 to 47 percent of subjects in the active treatment groups, compared with 65 percent of those receiving placebo.

Treatment groups included 51 subjects randomized to receive placebo, and 51, 49 and 50 subjects randomized to receive oxycodone/acetaminophen or valdecoxib 20 mg or 40 mg, respectively. A total of 136 subjects (46 who received placebo, 40 who received oxycodone/acetaminophen, 28 who received valdecoxib 20 mg, 22 who received valdecoxib 40 mg) received rescue medication. The cohort used in all efficacy analyses included all 201 subjects who were randomized to receive study treatment.

Efficacy analysis. Time to onset of analgesia. In both studies, subjects treated with valdecoxib 20 or 40 mg or with oxycodone/acetaminophen experienced a rapid onset of analgesia (median: 28–34 minutes) that was significantly shorter than that in those subjects treated with placebo (P < .05) (Table 3Go). In Study A, the log-rank test demonstrated that subjects receiving treatment with oxycodone/acetaminophen had a statistically significantly shorter time to onset of analgesia compared with those receiving valdecoxib 20 mg, but the mean difference of only three minutes was not clinically significant. No such difference was observed in Study B. In both studies, a higher proportion of subjects in the active treatment groups had meaningful analgesia than did subjects in the placebo group (Table 3Go). There was no consistent difference between the treatment groups in the proportion of subjects experiencing meaningful analgesia.


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  		TABLE 3 MEDIAN TIME TO ONSET OF MEANINGFUL ANALGESIA IN STUDY A AND STUDY B.

 
PID (categorical scale). Subjects receiving valdecoxib 20 mg or 40 mg or oxycodone/acetaminophen experienced a significantly greater reduction in PI (that is, higher mean PID scores) from baseline than did those receiving placebo from the 30-minute point (Study B) or the 45-minute point (Study A) until the end of the 24-hour evaluation period (P < .001) (Figures 1Go and 2Go).



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  		Figure 1. Mean pain intensity difference, or PID (categorical), scores over time, Study A. For oxycodone/acetaminophen, P < .001 vs. placebo from 45 minutes to 24 hours. For valdecoxib 20 milligrams, P < .01 vs. valdecoxib 40 mg from six to 24 hours. For valdecoxib 40 mg, P < .001 vs. oxycodone/acetaminophen from six to 24 hours.

 


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  		Figure 2. Mean pain intensity difference, or PID (categorical), scores over time, Study B. For oxycodone/acetaminophen, valdecoxib 20 milligrams and valdecoxib 40 mg, P < .001 vs. placebo from 30 minutes to 24 hours. For valdecoxib 20 mg, P < .01 vs. oxycodone/acetaminophen at most time points. For valdecoxib 40 mg, P < .01 vs. oxycodone/acetaminophen from six to 24 hours.

 
In both studies, valdecoxib-treated subjects experienced a peak reduction in PI relative to baseline (highest mean PID score) between three and six hours postdose (Figures 1Go and 2Go). This reduction in PI was maintained throughout the 24-hour evaluation period. In contrast, the peak reduction in PI relative to baseline for subjects receiving oxycodone/acetaminophen occurred earlier (two hours postdose) than it did with valdecoxib treatment in both studies, but it was not sustained; mean PID scores decreased from three to 10 hours postdose (Figures 1Go and 2Go).

In Study A, subjects receiving valdecoxib 20 mg experienced a reduction in PI relative to baseline comparable to that in oxycodone/acetaminophen–treated subjects from six to 24 hours postdose (Figure 1Go). In contrast, in Study B, subjects receiving valdecoxib 20 mg experienced a significantly greater reduction in PI compared with subjects receiving oxycodone/acetaminophen at most time points from six to 24 hours postdose (Figure 2Go). In both studies, subjects receiving valdecoxib 40 mg experienced significantly greater reductions in PI from baseline than did those receiving oxycodone/acetaminophen, from the six-hour point to the end of the 24-hour assessment period (P < .001, Study A, all time points, and Study B, most time points) (Figures 1Go and 2Go).

In Study A, subjects receiving valdecoxib 40 mg experienced a significantly greater reduction in PI relative to baseline than did those receiving the 20 mg dose from six to 24 hours postdose. However, in Study B, both doses of valdecoxib elicited comparable reductions in PI relative to baseline over 24 hours.

PPID. As shown by the mean PPID scores in both studies, all active treatments had a peak effect significantly greater than that of placebo. All active treatment groups had a comparable peak effect, with the exception of the valdecoxib 20-mg group in Study A, which had significantly lower mean PPID scores than did the oxycodone/acetaminophen and valdecoxib 40-mg groups (Table 4Go).


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  		TABLE 4 SUMMED AND PEAK PAIN INTENSITY AND PAIN RELIEF SCORES.

 
PR. The PR results mirrored those of the PID analyses. In both studies, subjects receiving active treatments experienced significantly greater levels of PR than did those receiving placebo, from 45 minutes postdose. However, while valdecoxib 40-mg treatment provided subjects with sustained PR over 24 hours, oxycodone/acetaminophen treatment did not.

PPR. These results mirrored the trends observed in the PPID analyses, confirming that valdecoxib 40 mg had a peak effect comparable to that of oxycodone/acetaminophen in each study (Table 4Go).

TOTPAR. In Study A, all active treatment groups had a mean TOTPAR (0–24 hours) score significantly greater than that for placebo. The valdecoxib 40-mg group had a significantly greater mean TOTPAR (0–24 hours) score than the oxycodone/acetaminophen and valdecoxib 20-mg groups. In Study B, both valdecoxib groups had significantly greater mean TOTPAR (0–24 hours) scores than did the oxycodone/acetaminophen group (Table 4Go).

SPID (categorical scale). In both studies, the mean SPID scores showed that subjects receiving active treatments experienced significantly greater levels of analgesia than did those receiving placebo, at all intervals (P < .001). In both studies, the mean SPID scores increased at each time point up to 24 hours for each treatment group. In addition, and consistent with the TOTPAR findings (Table 4Go), subjects receiving valdecoxib 40 mg experienced greater levels of analgesia than did those receiving oxycodone/acetaminophen (P < .05). This difference was significant from 12 to 24 hours postdose in both studies. In Study A, subjects receiving valdecoxib 40 mg experienced significantly more PR than did those receiving the valdecoxib 20 mg-dose. However, in Study B, subjects receiving both doses of valdecoxib experienced comparable levels of analgesia. In each study, the pattern of differences in mean SPID scores between groups at six hours postdose also was observed at every other time point.

Time to rescue medication. Significantly fewer subjects receiving active treatments required rescue medication compared with those receiving placebo in both studies. In addition, fewer subjects receiving valdecoxib 20 mg (46–57 percent) or 40 mg (24–44 percent) required rescue medication than those receiving oxycodone/acetaminophen (55–78 percent) (Table 5Go). In Study A, subjects receiving valdecoxib 40 mg experienced a longer median time to rescue analgesia (> 24 hours) than those receiving oxycodone/acetaminophen (11 hours 17 minutes), and placebo (one hour five minutes), according to log-rank analyses (Table 5Go). Similarly, in Study B, log-rank analyses revealed that subjects receiving either dose of valdecoxib experienced significantly longer median times to rescue analgesia relative to subjects treated with oxycodone/acetaminophen or placebo.


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  		TABLE 5 MEDIAN TIME TO RESCUE MEDICATION IN STUDY A AND STUDY B.

 
Patients’ global evaluation of study medications. In both studies, significantly more subjects in the active treatment groups rated their study medication as good or excellent than did those in the placebo group (P < .001). In Study A, only 25 percent of subjects receiving placebo rated their medication as good or excellent, compared with 66 to 80 percent of those in the active treatment groups. We observed a similar result in Study B.

Safety. In both studies, subjects treated with valdecoxib reported significantly fewer adverse events than did those in the placebo or oxycodone/acetaminophen groups. When the safety cohorts from both studies were pooled, significantly fewer adverse events were experienced by subjects receiving valdecoxib 20 mg or 40 mg (36 and 27 percent, respectively) than by those receiving placebo (53 percent) (P ≤ .01). Significantly more adverse events were experienced by subjects treated with oxycodone/acetaminophen (70 percent) compared with those receiving placebo (53 percent) (P = .02) or valdecoxib 20 mg or 40 mg (P < .001). Most adverse events were mild to moderate in severity, and none resulted in discontinuation of the study medication.

Common adverse events reported in more than 5 percent of subjects included nausea, dizziness, headache, vomiting and somnolence (Table 6Go). Significantly more subjects in the oxycodone/acetaminophen groups reported adverse events commonly associated with opioid use such as dizziness (P < .001), vomiting and somnolence (both P < .05) than in the placebo groups (Table 6Go). Subjects treated with valdecoxib 20 mg and 40 mg, relative to those receiving oxycodone/acetaminophen, experienced a significantly lower incidence of opioid-associated adverse events—such as nausea, dizziness, vomiting and somnolence (the last being significantly lower only among those who received valdecoxib 20 mg) (P < .05). Only one cardiovascular adverse effect was reported in both trials. One patient treated with oxycodone/acetaminophen experienced hypertension.


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  		TABLE 6 INCIDENCE OF ADVERSE EVENTS: POOLED STUDY A AND STUDY B DATA.

 

   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
The results of both of these studies demonstrate that valdecoxib is an effective and potent analgesic in the treatment of moderate-to-severe acute pain resulting from oral surgery. While similar to oxycodone/acetaminophen in terms of time to onset of analgesia and peak analgesic effect, a 40-mg dose of valdecoxib had a longer duration of action (at least 24 hours) than did oxycodone/acetaminophen (five hours). These data suggest that in the great majority of patients who undergo oral surgery, one oral dose of valdecoxib will be sufficient to provide satisfactory analgesia over a 24-hour period. Furthermore, 20- and 40-mg doses of valdecoxib had a tolerability profile superior to those of both placebo and oxycodone/acetaminophen in subjects after oral surgery.

In both studies, subjects receiving either dose of valdecoxib experienced a rapid time to onset of analgesia, comparable with that of oxycodone/acetaminophen. While the PR provided by the two drugs was similar up to five hours postdose, valdecoxib 40 mg (and, in Study A, valdecoxib 20 mg) provided a sustained level of analgesia over the 24-hour evaluation period that was superior to that of oxycodone/acetaminophen from six hours postdose. The sustained analgesic action of valdecoxib is considerably longer than that predicted by its elimination half-life of eight to 11 hours.15 This difference between the duration of the pharmacodynamic effect and the pharmacokinetic half-life of valdecoxib may be attributable to the slow off rate of valdecoxib from the COX-2 enzyme (T. Maziasz, Ph.D., director, COX-2 Research, Pharmacia Corp., Skokie, Ill., unpublished data, July 2001). Other drugs known to have a pharmacodynamic effect considerably greater than that predicted by their pharmacokinetics include aspirin. A once-daily regimen of low-dose aspirin (40–80 mg daily) has an anticlotting effect that significantly reduces the risk of experiencing myocardial infarction.25 In one study, daily aspirin doses of 40 or 80 mg reduced serum thromboxane ß2 (TxB2, a marker of platelet-derived COX-1 activity) levels by 100 percent, and by 78 to 84 percent if administered only once every three days.25 This marked pharmacodynamic effect is observed despite estimates of an elimination half-life of only 0.4 hours in healthy men receiving a single dose of aspirin 80 mg.26

In Study A, subjects treated with valdecoxib 40 mg experienced a level of analgesia significantly greater than that experienced by those receiving the 20-mg dose. In contrast, in Study B, the two valdecoxib doses were equally effective. The differing response to the suboptimal 20-mg valdecoxib dose likely reflects the greater proportion of subjects experiencing severe surgical trauma at baseline in Study A (52 percent) compared with Study B (2 percent). Hence, a 40-mg dose of valdecoxib, which is as well-tolerated as a 20-mg dose, appears to be the optimal initial dosage for subjects with acute pain after oral surgery.

Valdecoxib administration resulted in significantly fewer opioid-related adverse events—such as dizziness, nausea, vomiting and somnolence—than did oxycodone/acetaminophen administration. This is consistent with the observation that valdecoxib does not interact with any of the opioid receptors in vitro (T. Maziasz, Ph.D., director, COX-2 Research, Pharmacia Corp., unpublished data, July 2001).

Combination products, including opioids and nonopioids, were introduced in the early 1980s in an attempt to enhance the level of analgesia and reduce the incidence of adverse events associated with single analgesics by combining two analgesics that had different mechanisms of action.27 Preliminary evidence supported the rationale27,28; however, combinations of acetaminophen with codeine or oxycodone have been associated with a considerably greater incidence (up to fourfold greater) of adverse events than have conventional NSAIDs such as ibuprofen, ketorolac and aspirin.20,29 COX-2–specific inhibitors are well-tolerated and are not anticipated to elicit the side effects characteristic of the opioids. Furthermore, COX-2–specific inhibitors have been shown to have a considerably lower incidence of the platelet-dysfunction–related and GI adverse events than those seen with conventional NSAIDs (such as ibuprofen) that nonselectively inhibit both COX-1 and COX-2.6,11–12


   CONCLUSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
These two studies suggest that a single dose of the COX-2–specific inhibitor, valdecoxib, is as rapidly acting and effective as oxycodone/acetaminophen in treating post–oral surgery pain. Valdecoxib also has a longer duration of analgesic action than that of oxycodone/acetaminophen and, therefore, offers a more convenient dosing interval. The analgesic efficacy of the valdecoxib 40-mg dose is superior to that of the 20-mg dose. Furthermore, in each study, both doses of valdecoxib had a similar tolerability profile that was superior to that of oxycodone/acetaminophen. These data demonstrate the clinical utility of valdecoxib in the treatment of acute postsurgical pain.


   FOOTNOTES
 

Dr. Daniels is executive medical director, Clinical Site Operations, SCIREX Corp., Austin, Texas.


Dr. Desjardins is senior vice president, Clinical Site Operations, SCIREX Corp., Austin, Texas.


Dr. Talwalker is director, Biostatistics, Pharmacia Corp., Skokie, Ill.


Dr. Recker is senior director, Medical Development, Pharmacia Corp., Skokie, Ill.


Dr. Verburg is clinical vice-president, Medical Development, Pharmacia Corp., 5200 Old Orchard Road, Skokie, Ill. 60077, e-mail "kenneth.m.verburg{at}pharmacia.com". Address reprint requests to Dr. Verburg.


This study was co-sponsored by the Pharmacia Corp., Skokie, Ill., and Pfizer Inc., Groton, Conn.


The authors wish to thank Mr. Doug Baum, program director; Drs. Donald Bandy, Dean Jasper and Franklin Bonasso, surgeon-subinvestigators; Ms. Diane Hallmark, R.N., and Ms. Stacy Mills, L.V.N., site managers; Ms. Kelle Simpson, R.N., M.B.A., project manager; and Alicia Bauman, R.N., B.S.N., Alice Arnold, R.N., and Carrie Smith, R.N., lead research coordinators, for their contributions to these projects.


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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