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J Am Dent Assoc, Vol 131, No 12, 1729-1737.
© 2000 American Dental Association |  |
CLINICAL PHARMACOLOGY |
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSEFFICACY ASSESSMENTSSTATISTICAL EVALUATIONRESULTSTOLERABILITYDISCUSSIONCONCLUSIONREFERENCES |
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Methods. The six studies included doses of rofecoxib ranging from 7.5 to 500 milligrams. Maximal analgesic doses of a nonsteroidal anti-inflammatory drug, or NSAID, either naproxen sodium (550 mg) or ibuprofen (400 mg), were used as active comparators in each study. Analgesic efficacy was assessed with the use of validated self-administered questionnaires. The primary endpoint in each study was the total pain relief over the eight-hour postdose period. Additional endpoints were used to characterize the onset of analgesia and peak analgesic effect.
Results. The results of these studies demonstrated that the efficacy of rofecoxib was dose-related, with 50 mg being consistently more effective than placebo for all measures of analgesic efficacy. Moreover, 50 mg was the lowest dose that reproducibly demonstrated an analgesic effect comparable to the effect of maximum single analgesic doses of NSAIDs.
Conclusion. The results of these studies support the recommended dose of 50 mg of rofecoxib once daily for the management of pain.
Clinical Implications. Rofecoxib, at a dose of 50 mg, is effective in the management of postoperative dental pain.
The pain experienced after oral surgery is an accepted model for the clinical evaluation of acute analgesic medications.1 Current data support the hypothesis that such acute pain is caused by increased prostaglandin synthesis. For example, the increase of prostaglandin E2 within the oral surgical site correlates with increased pain following extraction of impacted third molars.2 Prostaglandin synthesis in humans is catalyzed by two distinct isoforms of cyclooxygenase, or COX—COX-1 and COX-23,4—which likely mediate distinct biological processes. COX-1 is constitutively active throughout the body.3–5 In contrast, under basal conditions, COX-2 expression is limited, including the brain6 and kidney,7 but is markedly upregulated by a variety of inflammatory mediators.3 These distinct expression patterns have led to the proposal that prostaglandins produced by COX-1 are largely responsible for physiological functions,8 while COX-2–derived prostaglandins mediate pathophysiological and inflammatory processes, including pain.4,8
The pattern of induction and localization for COX-2 indicates that it is primarily responsible for the synthesis of prostanoids and mediation of responses to pathological processes, such as inflammation, pain and fever. In contrast, the constitutive expression pattern of COX-1 suggests that this isoform is responsible for the routine physiological functions of prostanoids, including gastric mucosal protection and vascular homeostasis. By specifically inhibiting COX-2 activity, rofecoxib is intended to have anti-inflammatory and analgesic effects, within the therapeutic dose range, without blocking the physiological functions of the COX-1 isoform.
In vitro and ex vivo assays have shown that nonsteroidal anti-inflammatory drugs, or NSAIDS, nonspecifically inhibit both the COX-1 and COX-2 isoforms.8–14 In contrast, rofecoxib has been characterized as specifically inhibiting COX-2.15 Previous reports have documented that 50 mg of rofecoxib had analgesic efficacy comparable to that of maximal single analgesic doses of NSAIDs (naproxen sodium or ibuprofen) in treating both primary dysmenorrhea and postoperative dental pain.15–17 Additional data demonstrated that 50 mg of rofecoxib had analgesic efficacy greater than that of placebo and generally similar to that of naproxen sodium in treating postorthopedic surgical pain (A. Reicin, J. Brown, M. deAndrae, Merck & Co. Inc., unpublished data, August 2000). However, these reports did not provide the full spectrum of data available on the analgesic efficacy of various doses of rofecoxib.
In this article, we review all six placebo-controlled trials completed between 1994 and 1998 that were designed to evaluate the single-dose analgesic efficacy of rofecoxib in the treatment of postoperative dental pain. The six studies consisted of one pilot study (protocol 115), two phase 2 studies (protocols 2 and 3) and three phase 3 studies (protocols 4,16 5 and 6). All included doses of rofecoxib ranging from 7.5 to 500 mg (further explanation of the protocols is provided in the Results section below). Maximal analgesic doses of an NSAID, either naproxen sodium (550 mg) or ibuprofen (400 mg), were used as active comparators in each of the studies. The complete results of two of these studies (protocols 1 and 4) have been published elsewhere.15,16
Patients were eligible for enrollment if they were 18 years of age or older (protocols 1, 2 and 3) or 16 years of age or older (protocols 4, 5 and 6). Patients must have been scheduled to undergo removal of two or more third molars (one or two molars in protocol 1), at least one of which was partially embedded in bone and was a mandibular impaction. Women were required to be post-menopausal, surgically sterilized or using an accepted form of birth control (that is, oral contraceptives, double-barrier contraception or abstinence); in addition, they must have had a negative pregnancy test result on study entry (in protocol 1, however, only women who could not bear children were eligible for enrollment).
Exclusion criteria included allergy or intolerance to naproxen sodium, aspirin, ibuprofen, indomethacin, other NSAIDs, acetaminophen or hydrocodone; history of asthma in association with nasal polyps; recent history of chronic analgesic or tranquilizer use or dependency; and alcohol abuse. Also excluded were patients who had uncontrolled hypertension (or a history of hypertension in protocol 1); uncontrolled diabetes mellitus (or a history of diabetes mellitus in protocol 1); renal disease; stroke or neurological disorder; cardiovascular, hepatic or neoplastic disease; or clinically significant abnormalities evident on the prestudy clinical examination or significantly abnormal laboratory safety test results (tests included a complete blood cell count, serum chemistries and urinalysis). Patients were not allowed to take any analgesics during the six hours before surgery.
On confirmation of eligibility, patients underwent the dental extraction procedures; generally, both local and systemic anesthetics were allowed. All patients received surgical anesthetics, although the type of anesthetic varied between studies. In protocol 1, only lidocaine with epinephrine was used for all patients. In protocols 3 and 6, only lidocaine with epinephrine, nitrous oxide, or both were used for all patients. The remaining studies used various other drugs, such as ketamine hydrochloride, atropine, mepivacaine hydrochloride, methohexital sodium, fentanyl, midazolam and diazepam in addition to the anesthetics used in protocols 1, 3 and 6.
The study investigator, as noted above, recorded the number of teeth removed during the procedure and the duration of the procedure (in minutes); this information was not recorded in protocol 1. On development of moderate-to-severe postoperative pain, patients were randomized, by means of a computer-generated allocation schedule, to receive a dose of rofecoxib, an active comparator (individual studies used either naproxen sodium [550 mg] or ibuprofen [400 mg]) or placebo. In protocol 1, patients remained in the study unit and provided efficacy assessments for the first six hours after receiving the drug, and no additional efficacy assessments were provided. In the other five studies, patients remained in the study unit and provided efficacy assessments for the first eight hours after receiving the drug; the remaining assessments were performed either in the study unit (protocol 2) or on an outpatient basis (protocols 3, 4 and 5).
During the postdose period, a combination analgesic consisting of acetaminophen plus hydrocodone bitartrate was administered one or more times as "rescue medication" if the patient experienced inadequate pain relief with the study medication. Patients were asked to avoid using rescue analgesics during the first 90 minutes after they received the study drug to allow it to exhibit an effect. The investigator recorded the date and time of the first use of rescue medication during the postdose study period.
Protocols 1 and 2 used a formulation of rofecoxib that differs from that which is currently marketed. Although this earlier formulation revealed a somewhat lower maximal plasma concentration, or Cmax (about 20 percent), overall bioavailability was similar to that of the current formulation (94 percent), and the time to maximum concentrations was the same (J. Schwartz, PharmD., Merck & Co., unpublished data, 1998).
Investigators used stopwatches at the time of dosing for each patient. In protocols 1, 2 and 3, a single stopwatch was used to record the elapsed time until the patient first experienced meaningful pain relief. In protocols 4, 5 and 6, a two-stopwatch method was used16 in which the investigator recorded the elapsed time until the patient first experienced perceptible pain relief and the elapsed time until the patient first experienced meaningful pain relief (according to his or her own interpretation). If a patient did not report experiencing meaningful pain relief within four hours after the study drug was administered, or requested rescue analgesia, the investigator stopped using the stopwatches for that patient.
We calculated the following indexes of drug efficacy16 from the scores and times described above:
In protocol 4, rofecoxib demonstrated sustained analgesic efficacy over the 24-hour postdose period,16 which supports the recommended once-daily dosing with rofecoxib.
The primary endpoint, or measure, of the studies was TOPAR8 or TOPAR6 (in protocol 1). With the exception of protocol 1 (a pilot study), these studies were designed with sufficient power (
We defined confirmed perceptible pain relief as the time at which perceptible pain relief was achieved, provided that the patient also achieved meaningful pain relief (again, as interpreted by the patient). If perceptible pain relief was achieved without associated meaningful pain relief, a value of four hours (the time at which use of the stopwatch was stopped) was used in the survival analysis of stopwatch times. Analyses of the data were based on the intention-to-treat approach (that is, according to the drug that the patient was randomized to receive), and the primary comparison was between the TOPAR8 (or TOPAR6 in protocol 1) scores produced by rofecoxib and those produced by placebo. Differences were considered statistically significant at P < .05 (two-tailed).
PATIENTS AND METHODS
TOP
ABSTRACT
PATIENTS AND METHODS
EFFICACY ASSESSMENTS
STATISTICAL EVALUATION
RESULTS
TOLERABILITY
DISCUSSION
CONCLUSION
REFERENCES
All trials were double-blind, randomized, placebo- and active-comparator–controlled, parallel-group studies; each was conducted at a single site. Each study was approved by an appropriate institutional review board and all patients gave written informed consent before participating. The studies were performed at these clinical research centers: SCIREX (protocols 1, 2 and 5 [D. Mehlisch]), PPD-Pharmaco (protocols 3 and 6 [J. Fricke]) and Jean Brown Associates (protocol 4 [J. Brown]).
EFFICACY ASSESSMENTS
TOP
ABSTRACT
PATIENTS AND METHODS
EFFICACY ASSESSMENTS
STATISTICAL EVALUATION
RESULTS
TOLERABILITY
DISCUSSION
CONCLUSION
REFERENCES
Each patient evaluated his or her pain symptoms at specified time points (0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12 and 24 hours after administration of the study drug) and recorded them in the patient diary using established rating scales.18 Pain intensity was recorded on a four-point scale (0 = none to 3 = severe) at baseline and at the same specified times following the administration of a single dose of the study drug. Pain relief was recorded on a five-point scale (0 = none to 4 = complete) at the same postdose time points. Patients also recorded the date and time at which they took any rescue medication. In addition, patients rated the study drug using a five-point global evaluation scale (0 = poor to 4 = excellent) at specified post-dose time points.
1—this represents the time (in hours) that it took for the patient’s pain to decrease from "severe" to at least "moderate" or from "moderate" to at least "slight";
95 percent) (based on a two-sided test with a significance level 
= .05) to detect a difference in TOPAR between any treatment group and the placebo group. However, there were no prospective hypotheses to distinguish between rofecoxib and the active comparator.
STATISTICAL EVALUATION
TOP
ABSTRACT
PATIENTS AND METHODS
EFFICACY ASSESSMENTS
STATISTICAL EVALUATION
RESULTS
TOLERABILITY
DISCUSSION
CONCLUSION
REFERENCES
We used an analysis of variance model in the analysis of TOPAR8 (or TOPAR6 for protocol 1), SPID8 (or SPID6 for protocol 1), patient’s global evaluation score, peak pain relief and other continuous variables. This model included treatment and baseline pain intensity scores as factors. Cox proportional hazards regression model,19 non-parametric log-rank test and the Kaplan-Meier estimates were used in the analysis of stopwatch times and time to PID 1.
RESULTS
TOP
ABSTRACT
PATIENTS AND METHODS
EFFICACY ASSESSMENTS
STATISTICAL EVALUATION
RESULTS
TOLERABILITY
DISCUSSION
CONCLUSION
REFERENCES
Table 1
shows the treatment groups included in each study protocol. The overall demographic data for patients in each study are shown in Table 2. Within each study, the demographic profiles were clinically comparable between the treatment groups (data not shown). Of the 1,284 patients who enrolled, 719 (56 percent) were female, 937 (73 percent) were white , 193 (15 percent) were Hispanic and the remainder were of other ethnic origins. The mean age of patients was 22.1 years (range, 16 to 48 years). Nine hundred fifty (74 percent) of the patients had a baseline pain intensity score of "moderate" and 334 (26 percent) had a score of "severe." Some differences existed between the studies with regard to baseline demographic data, such as the mean number of teeth removed and the distribution of moderate vs. severe pain at baseline (Table 2), but all demographic data were clinically comparable across treatment groups within each protocol (data not shown).
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The primary endpoint for each study, TOPAR8 or TOPAR6 (in protocol 1), was derived from the pain relief scores, as the summed time-weighted pain relief scores over eight hours (or six hours). The figure shows the TOPAR8 scores for each treatment group (presented as the difference from placebo scores) in each study and are representative of the endpoints assessing overall analgesic effect. Results for the other endpoints that assess overall analgesic effect, including patient global evaluation and SPID8, are not presented, but in all studies at all doses, the results for these endpoints generally were consistent with those for TOPAR8 (or TOPAR6).
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shows the results for representative endpoints that assessed these two analgesic characteristics for each treatment group in each study. Moreover, in all studies at all doses, additional endpoints that assessed these same characteristics (that is, time to PID 1 as a measure of analgesia onset and peak PID as a measure of peak analgesic effect) exhibited results that generally were consistent with those presented in Table 3.
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). It is important to note that all three doses also demonstrated analgesic efficacy generally similar to that of ibuprofen (400 mg).
Protocol 2.
This protocol was designed on the basis of the results of protocol 1 and therefore explored the analgesic efficacy of rofecoxib doses approximating 50 mg. Four doses of rofecoxib (7.5, 25, 50 and 100 mg) were compared with placebo and with naproxen sodium (550 mg). The results of this study showed a good relationship between the analgesic effect achieved and the dose of rofecoxib administered (Figure and Table 3), with the 7.5- and 25-mg doses generally less effective than the 50- and 100-mg doses. Rofecoxib exhibited maximal efficacy at the 50-mg dose. The efficacy of the 100-mg dose was numerically superior to that of 50 mg, as assessed by TOPAR8, but the difference was minimal and not statistically significant. Moreover, neither the onset of analgesia nor the peak analgesic effect of the 100-mg dose of rofecoxib was significantly different from that of the 50-mg dose (Table 3). The analgesic effect of 50 mg generally was similar to that of naproxen sodium (550 mg) (Figure and Table 3).
Protocol 3.
This protocol was a confirmatory study that examined doses of 12.5, 25 and 50 mg of rofecoxib. The results of this study generally are consistent with those of protocol 2 (Figure and Table 3).
Protocols 4, 5 and 6.
These protocols primarily were intended to be confirmatory, phase 3 studies of the analgesic efficacy of the 50-mg dose of rofecoxib. The results of protocol 4, in which 50 mg was the only dose studied, have been presented in detail elsewhere.16 In brief, the results of protocol 4 demonstrated that 50 mg of rofecoxib was more effective than placebo at all endpoints examined and generally comparable in efficacy to ibuprofen (400 mg) (Figure and Table 3).
In addition to 50-mg doses, protocol 5 assessed 100- and 200-mg doses of rofecoxib, and protocol 6 included the 100-mg dose. Both protocols 5 and 6 confirmed the results of protocol 4 with regard to the efficacy of the 50-mg dose of rofecoxib; in both studies, 50 mg was more effective than placebo at all endpoints examined and generally comparable in efficacy to ibuprofen (400 mg) (Figure and Table 3).
Other results of protocol 5, however, were somewhat at odds with those of the previous dose-ranging studies (that is, protocols 1 through 4). The results of protocol 5 showed significantly greater TOPAR8 scores for both the 100- and 200-mg doses of rofecoxib compared with both the 50-mg dose and ibuprofen (400 mg) (Figure). However, neither 100 nor 200 mg of rofecoxib had an onset of analgesia that was significantly different from that of 50 mg of rofecoxib or ibuprofen (Table 3). Peak pain relief for both the 100- and 200-mg doses of rofecoxib was numerically greater than, but not significantly different from, that for the 50-mg dose, although both of the higher doses were significantly more effective than ibuprofen (400 mg) (Table 3). In contrast, the results of protocol 6 did not demonstrate a significant difference between 100 mg of rofecoxib and either 50 mg of the drug or ibuprofen in regard to TOPAR8 or to measures of analgesia onset or peak analgesic effect (Figure and Table 3).
Taken together, the results from protocols 5 and 6 are consistent with those from protocol 416 and confirm that the onset of analgesia is about 45 minutes (range, 0.6 to 0.9 hours or 36 to 54 minutes) for the 50-mg dose of rofecoxib.
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TOLERABILITY |
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TOPABSTRACTPATIENTS AND METHODSEFFICACY ASSESSMENTSSTATISTICAL EVALUATIONRESULTSTOLERABILITYDISCUSSIONCONCLUSIONREFERENCES |
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSEFFICACY ASSESSMENTSSTATISTICAL EVALUATIONRESULTSTOLERABILITYDISCUSSIONCONCLUSIONREFERENCES |
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Rofecoxib at 50 mg consistently provided analgesic efficacy similar to that of the comparator NSAID—either naproxen sodium (550 mg) or ibuprofen (400 mg)—at all endpoints, including those assessing overall efficacy, onset of efficacy and peak analgesic effect. In addition, 50 mg generally was the lowest dose of rofecoxib needed to achieve peak analgesic effect. Although the TOPAR8 scores from protocol 5 suggest that additional analgesic efficacy was achieved at doses above 50 mg, this conclusion was not supported by the TOPAR8 scores for the 100-mg dose in either protocol 2 or protocol 6. Moreover, measures of onset of analgesic efficacy and peak analgesic effect did not show a significant advantage for doses above 50 mg in any of the six studies.
NSAIDs such as ibuprofen and naproxen sodium are commonly used analgesics. As mentioned above, NSAIDs non-specifically inhibit both the COX-1 and COX-2 isoforms.8–14 In contrast, rofecoxib has been characterized as specifically inhibiting COX-2.15 In our studies, rofecoxib consistently resulted in peak analgesic efficacy comparable to that of the maximal, single analgesic dose of ibuprofen and naproxen sodium. This observation lends strong support to the hypothesis that the analgesic properties of dual COX-1/COX-2 inhibitors are due primarily to their ability to inhibit COX-2.
The ceiling analgesic effect is the maximum analgesic effect possible with medication and is assessed by peak pain relief. Even at the 500-mg dose of rofecoxib (10 times the clinical dose), peak pain relief was comparable to that of NSAIDs. This provides evidence that drugs that specifically inhibit COX-2 are comparable to dual COX-1/COX-2 inhibitors in regard to efficacy. Other recent clinical studies have demonstrated that rofecoxib has analgesic properties in the treatment of osteoarthritis20–22 that are comparable to those of high doses of NSAIDs,21,22 and that rofecoxib has analgesic properties comparable to those of dual COX-1/COX-2 inhibitors for both primary dysmenorrhea17 and post-orthopedic surgical pain (A. Reicin, J. Brown, M. deAndrae, Merck & Co. Inc., unpublished data, August 2000). Determining whether inhibition of COX-2 alone is sufficient for analgesic efficacy in other pain syndromes will require further studies with a drug that specifically inhibits COX-2, such as rofecoxib.
In our six single-dose studies, all doses of rofecoxib were well-tolerated by patients. The single-dose nature of these studies in young, healthy subjects does not allow a comparison of the long-term safety and tolerability of rofecoxib compared with NSAIDs. However, other clinical studies have found that the incidence of abnormalities of the gastrointestinal mucosa, as assessed by endoscopy, was substantially lower with 25 and 50 mg of rofecoxib administered once daily than with 800 mg of ibuprofen administered three times daily.23,24 In addition, in an overview analysis of all clinical trials performed with rofecoxib, Langman and colleagues25 found that the incidence of gastroduodenal perforations, ulcers and bleeding episodes was significantly lower with rofecoxib than with NSAIDs. Finally, although these were single-dose studies in young, healthy subjects, it is important to note that no case of hypertension or edema was reported in any study.
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CONCLUSION |
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TOPABSTRACTPATIENTS AND METHODSEFFICACY ASSESSMENTSSTATISTICAL EVALUATIONRESULTSTOLERABILITYDISCUSSIONCONCLUSIONREFERENCES |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTPATIENTS AND METHODSEFFICACY ASSESSMENTSSTATISTICAL EVALUATIONRESULTSTOLERABILITYDISCUSSIONCONCLUSIONREFERENCES |
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