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© 2001 International Anesthesia Research Society
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Abstract |
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Preoperative administration of analgesics may prevent or reduce hyperalgesia and inhibit inflammation and pain by reducing the synthesis of prostaglandins in response to surgical injury. We evaluated in this placebo-controlled study the analgesic efficacy and safety of single doses of parecoxib sodium (20, 40, and 80 mg IV) when administered before oral surgery. Efficacy assessments were recorded during the 24-h period after completion of surgery. All doses of parecoxib sodium were consistently and significantly superior to placebo as measured by time to rescue medication, proportion of patients requiring rescue medication, patient’s global assessment, and pain intensity. There were no significant differences between the Parecoxib Sodium 40- and 80-mg groups, suggesting that the analgesic effect of preoperatively administered parecoxib sodium reaches a plateau at 40 mg in this model. Forty-eight percent of the Parecoxib Sodium 40-mg group required rescue medication in the 24-h study period, compared with 93% of patients in the Placebo group. Overall, there were fewer adverse events in parecoxib sodium-treated patients compared with placebo. These findings suggest that preoperative administration of parecoxib sodium, the injectable prodrug of the cyclooxygenase-2 specific inhibitor valdecoxib, is effective, safe, and well tolerated for treating postoperative pain.
IMPLICATIONS: Preoperatively administered antiinflammatory analgesics should theoretically prevent the upregulation of nociception and inhibit inflammation and pain by reducing the synthesis of prostaglandins in response to surgery. The findings of this study demonstrate that preoperative administration of parecoxib sodium is both safe and effective for the treatment of pain after oral surgery.
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Introduction |
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Because pain after surgery is predictable, prevention of that pain is a better management strategy than treating the pain once it has occurred (1). Treating the patient before the development of significant pain is a more humane, enlightened approach to patient care and is consistent with the current trends toward more aggressive, preventive, and systematic approaches to pain management. Moreover, it has become recognized that the longer pain remains uncontrolled, the more sensitive the patient may become to painful stimuli; once nociception is upregulated through both central and peripheral mechanisms, perception of pain is altered, and hyperalgesia can occur (2). However, rapid analgesic intervention may prevent this so-called wind-up (upregulation) of the nociceptive system within the central nervous system.
Postoperative pain after extraction of impacted third molars is generally treated with conventional nonsteroidal antiinflammatory drugs (NSAIDs) or fixed-dose opioid combination analgesics. The most commonly used analgesic is a combination of acetaminophen and codeine (3), although there is a great deal of evidence that conventional NSAIDs are equally or more effective (4). Opioid combinations, although effective, are associated with many unwanted side effects, including sedation, altered mentation, psychomotor impairment, dizziness, and disturbance of gastrointestinal (GI) function, and therefore their efficacy is frequently limited by side effects and poor tolerability.
Conventional NSAIDs act by inhibiting cyclooxygenase (COX)-1 and COX-2 in a nonspecific manner, thereby inhibiting the production of prostaglandins. The analgesic and antiinflammatory activities of conventional NSAIDs have been attributed to the inhibition of COX-2, which is predominantly expressed at sites of inflammation and is involved in the induction of pain and inflammation (5). However, the concomitant inhibition of COX-1 by conventional NSAIDs interferes with normal platelet function, GI, and kidney, and may lead to clinically important adverse events, including upper GI bleeding, increased perioperative bleeding, and, less often, reduction in renal function. Because of these inherent, mechanism-based adverse effects of conventional NSAIDs, clinicians have been reluctant to use these drugs in the perioperative period, even including minor surgical procedures, such as oral surgery (6,7). In contrast to conventional NSAIDs, by sparing COX-1 function, COX-2 specific inhibitors provide the analgesic and antiinflammatory effects of conventional NSAIDs with an improved safety profile (8). This property makes COX-2-specific drugs potentially valuable analgesic drugs for use in the perioperative period for pain management. In addition, because they do not impair platelet aggregation, they may represent ideal drugs for preoperative administration for the prevention or reduction of postoperative pain.
There is a need for an effective analgesic that can be administered by injection for surgical patients who cannot tolerate oral medication or in whom preoperative oral medication is contraindicated (including those undergoing oral and maxillofacial surgery) but that does not have the side effects associated with conventional NSAIDs or opioids. Currently, the only injectable conventional NSAID available in the United States is ketorolac (Toradol®). However, ketorolac is associated with GI ulceration and bleeding, platelet dysfunction (decreased platelet aggregation and increased bleeding time), and acute renal failure (7,9–12). The risk of GI and operative site bleeding associated with ketorolac is dose related and is increased in patients older than 75 yr of age (12). This increased risk of GI toxicity led to ketorolac’s use being restricted to 5 days in the United States. Further, because of its effect on platelet aggregation, ketorolac is infrequently used for prophylactic analgesia before surgery (11).
The pyrazolone derivative metamizole sodium (dipyrone) is also used in several countries as an injectable nonnarcotic analgesic. However, the pyrazolone drugs were associated with fatal agranulocytosis cases, which led to their removal from the market in the United States (13). Metamizole is also associated with skin rashes and fixed drug eruptions (14).
Parecoxib sodium is an injectable prodrug of valdecoxib, a highly specific COX-2 inhibitor (15). It is hydrolyzed in the liver to the active moiety valdecoxib, which has a plasma time of maximal concentration as short as 16 min and is slowly cleared from the plasma, with an elimination half-life of approximately 8 h (16). Early clinical studies have shown that parecoxib sodium is well tolerated in doses up to 40 mg IM or 200 mg IV (16). It is currently in development for the management of moderate to severe pain. The objectives of this study were to compare the analgesic efficacy of preoperative doses of parecoxib sodium (20, 40, and 80 mg IV) and to assess the safety of these doses when administered preoperatively, using an oral surgery pain model.
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Methods |
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Patients aged between 18 and 45 yr requiring extraction of two ipsilateral impacted third molars with bone resection were eligible for the study. Patients were otherwise in good health.
Patients with uncontrolled chronic disease, a history of an upper GI ulcer within the past 6 mo, a history of chronic analgesic or tranquilizer use, or substance abuse within the 90 days preceding the study were excluded. Patients were also excluded if they had received acetaminophen within the 12 h preceding the administration of study medication, or any of the following types of medications within 24 h preceding the administration of study medication: tricyclic antidepressants, narcotic analgesics, antihistamines, tranquilizers, hypnotics, sedatives, conventional NSAIDs, or corticosteroids. Patients were required to abstain from alcohol or tobacco use for 6 h before and 24 h after dosing with study medication.
The study was a single-dose, randomized, double-blinded, placebo-controlled, parallel group clinical trial. Within a 14-day period before the administration of study medication (the pretreatment period), informed consent was obtained, and patients underwent medical history, physical examination, and clinical laboratory testing (including a pregnancy test for women of childbearing age). After eligible patients were randomized, a single dose of parecoxib sodium (20, 40, or 80 mg) or matching placebo was administered IV 30–45 min before the start of surgery (defined as the initial incision). Given the design of the study, which required preoperative dosing, an injectable conventional NSAID appropriate for preoperative administration could not be identified, and thus no active comparator treatment arm was included in the study. The study was conducted at the Texas Oral Surgery Association (Austin, TX). The protocol was approved by the Quorum Review IRB (Seattle, WA) and was conducted in accordance with the Declaration of Helsinki.
After the administration of study medication, the patient received a local anesthetic (7.2 mL of 2% lidocaine with 1:100,000 epinephrine) injected by the oral surgeon into the soft tissues surrounding the impacted molars. Nitrous oxide/oxygen sedation was also allowed, as necessary. If additional anesthesia was requested, the patient was withdrawn from the efficacy study, although safety data were still collected. The duration of surgery was limited to 10–30 min to avoid confounding the primary end point, median time to first rescue medication. Patients whose surgery took more time or less time were withdrawn from the efficacy evaluation.
Efficacy assessments were recorded during the 24-h period after completion of surgery. Patients were required to stay within the study center during this period. Each patient completed pain intensity (categorical as well as visual analog scale; VAS) assessments beginning at 30 min after closure of surgery and continuing at 2-h intervals from 2 to 24 h after surgery. The categoric pain intensity assessment was on a four-point scale (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain), and the VAS was 0–100 mm, where 0 mm is no pain and 100 mm is the worst imaginable pain. Patients were not awakened for assessments if they were asleep. Patients completed the global evaluation of study medication just before receiving any rescue medication (if required) or at the last hourly observation period (24 h after surgery) on a satisfaction scale of 1 to 4, where 1 = poor, 2 = fair, 3 = good, and 4 = excellent.
In the postsurgical period, rescue medication was permitted at any time when requested by the patient. Patients who took rescue medication completed no additional pain measurements, although they remained in the observation unit for 24 h after surgery. Time, type, and dose of rescue medication were recorded. Rescue medications allowed were oral acetaminophen 1000 mg; hydrocodone plus acetaminophen at one or two oral doses of 5 mg/500 mg or one dose of 7.5 mg/500 mg; or meperidine 50 mg plus promethazine 25 mg IM. At the follow-up visit, 5–9 days after surgery, the investigator or trained nurse observer reviewed with the patients the adverse event data that they had recorded in the diary, and laboratory evaluations were performed.
In contrast to analgesic trials, which evaluate the ability of drugs to treat pain, this study assessed the ability of the drug treatments to prevent postoperative pain. Hence the standard measures of pain-reducing analgesic activity based on a difference from baseline (for example, pain intensity difference or pain relief) were not used in this study. Analgesic efficacy was assessed on the basis of four key end points: 1) the median time to rescue medication (primary end point), 2) the proportion of patients who required rescue medication, 3) pain intensity, and 4) the patient’s global assessment of study medication.
General clinical safety was monitored by the incidence of treatment-emergent adverse events, physical examination, and changes from baseline in laboratory variables (obtained 24 h after surgery) and vital signs. Renal function was measured by serum creatinine and blood urea nitrogen.
The sample size calculation was based on the time to rescue medication end point. It was determined that 55 patients per group would be sufficient to detect (with 80% power and a type I error at 0.0167 adjusted for three comparisons) a difference of at least 3 h in the median time to rescue medication for active treatment versus placebo.
All efficacy analyses were performed on the intent-to-treat cohort, which included all randomized patients who took the preoperative dose within 30 to 45 min before surgery and completed the surgery within the required time limit (duration of 10 to 30 min). Time to rescue medication was analyzed with Kaplan-Meier survival estimates, with the adjustment described by Miller (17). The method of Simon and Lee (18) was used to calculate 95% confidence intervals for the median time to event, and log-rank tests were used to determine the statistical significance of differences in time to rescue medication between treatment groups.
The proportion of patients taking rescue medication was analyzed with Fisher’s exact test, and the patients’ global assessment and pain intensity assessments were analyzed with the Cochran-Mantel-Haenszel method for categoric data analysis. Pain intensity was analyzed with a last-observation-carried-forward approach, with the last observation defined as the observation just before receipt of study medication for those patients not completing 24 h of pain intensity assessment.
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Results |
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A total of 224 patients were randomized to receive study medication (56 in each group), and 214 completed the study over a 10-wk period. The treatment groups were statistically comparable with respect to baseline demographics, with the exception of maximum degree of impaction (Table 1). A significantly larger proportion of patients in the Parecoxib Sodium 80-mg group had partial bony impaction, compared with the other two groups (P = 0.031).
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Ten patients were withdrawn from the study after receiving study medication: two from each of the Placebo and Parecoxib Sodium 40- and 80-mg groups, and four from the Parecoxib Sodium 20-mg group. Nine of the patients were withdrawn for noncompliance with the protocol and one for a violation of the entry criteria. Six of these patients were excluded from the efficacy analyses; five patients were noncompliant with the inclusion criteria (time from drug administration to surgery or duration of surgery), and one received study medication but did not have surgery.
The median time to rescue medication was 2 h 51 min for patients receiving placebo, compared with a range of 6 h 17 min to more than 24 h for patients receiving one of the parecoxib sodium regimens. The 95% confidence intervals for each of the Parecoxib Sodium groups were distinct from those of the Placebo group, demonstrating a statistically significant difference in median time to rescue medication between each of the parecoxib sodium doses and placebo (Table 2). This observation was further supported by log-rank tests, which showed a statistically significant difference in distribution of time to rescue medication for each of the parecoxib sodium doses compared with placebo (Fig. 1).
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In the Parecoxib Sodium 40-mg group, the median time to rescue medication was more than 24 h, which was significantly longer than that of the Parecoxib Sodium 20-mg group (6 h 17 min). There was no significant difference between the Parecoxib Sodium 40- and 80-mg groups, despite the numeric difference favoring the 40-mg treatment.
A statistically significantly smaller proportion of patients in each of the active treatment groups took rescue medication compared with the Placebo group (P 
0.031; Table 2). Fewer than half of the patients (48%) in the Parecoxib Sodium 40-mg group required rescue medication in the 24-h study period, compared with 59% in the Parecoxib Sodium 80-mg group and 78% in the Parecoxib Sodium 20-mg group. In contrast, nearly all of the patients (93%) in the Placebo group took rescue medication. On the basis of pairwise comparisons, there were significant differences between the Parecoxib Sodium 20- and 40-mg groups, but not between the Parecoxib Sodium 20- and 80-mg or 40- and 80-mg groups.
Most (92%) of the patients receiving parecoxib sodium 40 mg rated the study medication as good or excellent (Fig. 2). This compares with 76% of patients in the 20-mg group and 81% of patients in the 80-mg group. Global evaluation scores for all three Parecoxib Sodium groups were significantly different from Placebo (P < 0.001), with only 32% of patients in the Placebo group rating the treatment as good or excellent.
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An increase in mean pain intensity (VAS) scores was observed in all groups over the first 4 h after surgery, largely reflecting the waning of effect of the local anesthetic (Fig. 3). However, from the 2-h assessment (i.e., 2 h after the completion of surgery) onward, all Parecoxib Sodium groups exhibited mean time-specific Pain Intensity scores that were statistically lower than those for Placebo. The mean scores for the Parecoxib Sodium 40-mg group were significantly lower than those for the Parecoxib Sodium 20-mg group at the 4-h assessment up to the 24-h assessment. There were no statistically significant differences between the Parecoxib Sodium 40- and 80-mg groups. The significance of pairwise comparisons at each time point was determined by using Fisher’s protected least significant difference procedure.
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Adverse events occurring during the 3 days after the administration of the study medication were reported for 39% of patients in the Placebo group, 30% of patients in the Parecoxib Sodium 20-mg group, 34% of patients in the Parecoxib Sodium 40-mg group, and 25% of patients in the Parecoxib Sodium 80-mg group. Most of these adverse events were mild to moderate in severity. No patient withdrew from the study because of adverse events. The adverse events reported by at least 5% of patients in any treatment group are summarized in Table 3. They include nausea, headache, dizziness, and vomiting. For each of these events, the incidence was most frequent in the Placebo group, suggesting an improvement in symptoms with parecoxib sodium compared with placebo. It is important to note that there were no cases of excessive surgical bleeding or renal dysfunction (serum creatinine >132.6 µmol/L, blood urea nitrogen >10.71 mmol/L, or both) related to use of study medication. There were no clinically significant changes in laboratory values observed during the study.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates that preoperative administration of parecoxib sodium is effective in reducing or eliminating postoperative pain after oral surgery. A single 20-, 40-, or 80-mg dose of parecoxib sodium showed superior analgesic efficacy compared with placebo on the basis of all of the efficacy assessments used in the trial. As measured by time to rescue medication, the proportion of patients requiring rescue medication, patient’s global assessment, or pain intensity, all doses of parecoxib sodium were statistically significantly superior to placebo in a consistent manner. Because each of these efficacy assessments measured different aspects of the patient’s pain experience and response to therapy, the overall interpretation of the results strongly indicates the effectiveness of preoperative administration of parecoxib sodium for the management of postoperative pain.
There were no significant differences between the Parecoxib Sodium 40- and 80-mg groups, suggesting that the analgesic effect of preoperatively administered parecoxib sodium reaches a plateau and that doses larger than 40 mg provide no additional analgesic benefits. The data do not support the conclusion of a paradoxical reduction of analgesic effect with larger doses, insofar as there was no statistically significant difference between 40 and 80 mg for any efficacy measure. Rather, these results are consistent with data from another oral surgery study with postoperative administration of parecoxib sodium in which a plateau of analgesic efficacy was demonstrated at the 40-mg dose level (19). The data further indicate that the 20-mg dose is an effective dose, although perhaps less so than the 40-mg dose.
The findings of this trial do not conclusively demonstrate a true preemptive analgesic effect of preoperatively-administered parecoxib sodium. Because the trial did not compare the analgesic efficacy of preoperative versus postoperative administration, it does not directly address true preemptive efficacy. Oral surgery studies of the effectiveness of postoperative administration of parecoxib sodium have demonstrated comparable analgesic efficacy to that seen in this trial (19,20). At fully effective doses (40–100 mg IV) of parecoxib sodium, the time to rescue medication was between 10 and 15 hours (19,20). Furthermore, parecoxib sodium 20 and 40 mg, IM and IV, was as effective as the largest recommended dose of ketorolac, 60 mg IM, in terms of both onset and magnitude, and at the larger dose it had a significantly longer duration of analgesic activity (20). However, because none of those trials contained a preoperative treatment arm, no direct comparison can be made between these approaches. Similarly, this trial included no postoperative treatment arm, thus also preventing any firm conclusions about the potential advantages of preoperative compared with postoperative therapy for pain management. Nonetheless, the results of this trial do indicate that preoperative treatment is clearly no less effective than postoperative treatment.
Other trials have evaluated the analgesic effectiveness of preoperatively-administered conventional NSAIDs in oral surgery. The results have been mixed, although some trials have demonstrated that this therapy can be effective (21–24). As with this trial, there has not been a consistent direct comparison of preoperative with postoperative administration. Where this has been performed, the results have been inconclusive because of a number of factors, including flawed trial design, choice of pain models, and inadequate statistical power (24,25).
Preoperatively-administered parecoxib sodium was well tolerated in this relatively healthy and young (18 to 41 years) population. Overall, there were somewhat fewer adverse events in parecoxib sodium-treated patients compared with placebo. It is interesting to note that the incidence of symptoms that are typically associated with surgery and anesthesia (headache, nausea, and vomiting) was less frequent in each of the three Parecoxib Sodium groups than in the Placebo group. Although this observation may be caused by the differential need for narcotic-containing rescue medication, it may also suggest not only that parecoxib sodium was an effective analgesic, but also that its preoperative administration may have the added benefit of improving the overall patient tolerability of surgery by reducing such symptoms. Whether this is caused simply by analgesic effects or by other factors related in some way to the antiinflammatory effects of parecoxib sodium is not clear.
Parecoxib sodium has no effect on platelet aggregation (26). Although the potential for excess surgical bleeding is very limited with oral surgery of this type, it is an important finding in this trial that with preoperative administration of parecoxib sodium there was no evidence of exaggerated or prolonged bleeding, consistent with the COX-2-specific, COX-1-sparing effects of parecoxib sodium. These results thus support the safe use of preoperative parecoxib sodium from the perspective of the absence of hemostatic impairment, an important advantage compared with conventional NSAIDs.
In conclusion, preoperative administration of parecoxib sodium before oral surgery is effective, safe, and well tolerated, providing significantly more analgesia and symptom control compared with placebo. These findings support the potential use of this injectable COX-2 selective drug for the preventive management of postoperative pain.
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Acknowledgments |
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Sponsored by GD Searle, Division of Pharmacia, and conducted at the Central Texas Oral Surgery Association, Austin, TX.
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References |
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