Paul J. Desjardins

Comparison of Rofecoxib and Celecoxib, Two Cyclooxygenase-2 Inhibitors, in Postoperative Dental Pain: A Randomized, Placebo- and Active-Comparator- Controlled Clinical Trial

Pain is a common complaint, often occurring in conjunction with inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesic agents in ambulatory patients. In recent studies, the cyclooxygenase-2 (COX-2) inhibitor rofecoxib demonstrated analgesic effects similar to those of NSAIDs in the treatment of acute pain and primary dysmenorrhea. The present randomized, single-dose, double-blind, double-dummy, placebo- and active-comparator-controlled, parallel-group study was undertaken to compare the analgesic efficacy of the COX-2 inhibitors rofecoxib 50 mg and celecoxib 200 mg with that of ibuprofen 400 mg and placebo in patients with postoperative dental pain. Two hundred and seventy-two patients experiencing pain after the removal of > or =2 third molars were randomized according to pain severity (moderate vs severe) to receive a single dose of placebo (n = 45), rofecoxib 50 mg (n = 90), celecoxib 200 mg (n = 91), or ibuprofen 400 mg (n = 46). Using a patient diary, patients recorded pain intensity, pain relief, and global evaluations throughout the 24-hour period after dosing. The overall analgesic effect, onset of action, peak effect, and duration of effect were evaluated, with the primary end point being total pain relief over 8 hours (TOPAR8). The safety profile was assessed on the basis of physical findings, laboratory results, and spontaneous reports of adverse experiences. The results showed that compared with celecoxib, rofecoxib had superior analgesic effects on all measures of analgesic efficacy, including overall analgesic effect (TOPAR8, 18.3 vs. 12.5; P<0.001), time to onset of effect (30 vs. 60 minutes; P = 0.003), peak pain relief (score, 2.8 vs 2.3; P<0.05), and duration of effect (>24 vs. 5.1 hours; P<0.001). In addition, rofecoxibs analgesic efficacy was similar to that of ibuprofen (TOPAR8, 18.3 vs. 17.0; P = 0.460), but the duration was longer (P<0.05); with ibuprofen, the time to on set was 24 minutes, peak pain relief score was 2.9, and duration of analgesic effect was 8.9 hours. The safety profile was similar across all treatment groups. Thus rofecoxib provided analgesic efficacy superior to that of celecoxib and comparable to that of ibuprofen in the treatment of patients with acute postoperative dental pain.

Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study.

BACKGROUND:Tapentadol is a novel, centrally acting analgesic with two modes of action, combining mu-opioid agonism and norepinephrine reuptake inhibition in a single molecule. We compared the efficacy and tolerability of tapentadol and a standard dose of morphine with placebo in a model of moderate-to-severe postoperative dental pain. METHODS:Patients undergoing mandibular third molar extraction and experiencing moderate-to-severe pain postsurgery were randomized to receive single, oral doses of tapentadol HCl (25, 50, 75, 100, or 200 mg), morphine sulfate (60 mg), ibuprofen (400 mg; used to establish model sensitivity), or placebo. Mean total pain relief over 8 h (TOTPAR-8) was the primary end point. Secondary end points included mean total pain relief over 4 h (TOTPAR-4) and onset of analgesia. Pairwise comparisons of study drug to placebo were assessed using the Fisher least significant difference test. Adverse events were recorded. RESULTS:Four hundred patients were randomized to treatment and completed the study. Compared with placebo, mean TOTPAR-8 was significantly greater for tapentadol HCl 50 mg (P = 0.041), 75 mg (P = 0.001), 100 mg (P < 0.001), and 200 mg (P < 0.001); morphine sulfate 60 mg (P < 0.001); and ibuprofen 400 mg (P < 0.001) in a nonparametric analysis of the primary end point. The significantly higher TOTPAR-8 score for ibuprofen compared with placebo established the sensitivity of the model. Mean TOTPAR-4 was higher and onset of action appeared more rapid for tapentadol HCl 200 mg than morphine sulfate 60 mg. Pain relief scores with morphine sulfate 60 mg were between those of tapentadol HCl 100 and 200 mg. The incidence of nausea and vomiting appeared to be lower with all doses of tapentadol HCl compared with morphine sulfate 60 mg, but was not statistically significant. CONCLUSION:Single oral doses of tapentadol 75 mg or higher effectively reduced moderate-to-severe postoperative dental pain in a dose-related fashion and were well-tolerated relative to morphine. These data suggest that tapentadol is a highly effective, centrally acting analgesic with a favorable side effect profile and rapid onset of action.

Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: A randomized, placebo-controlled clinical trial

BACKGROUND Rofecoxib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. OBJECTIVE The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. METHODS In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate to severe pain after the surgical extraction of > or = 2 third molars were randomized to receive a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPAR8) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2-stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. RESULTS A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% experienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR24 was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with enteric-coated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and >4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (>24 hours vs 1 hour and 37 minutes). Enteric-coated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, although the rofecoxib group had a significantly lower incidence of clinical and drug-related adverse events than the enteric-coated diclofenac sodium group. CONCLUSIONS A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours.

A randomized, double-blind, parallel-group study comparing the analgesic effect of etoricoxib to placebo, naproxen sodium, and acetaminophen with codeine using the dental impaction pain model.

Objective:To compare the overall analgesic effect, including time to onset, peak and duration of effect for etoricoxib 120 mg, a new COX-2 selective inhibitor, in patients with acute pain to that of placebo. Naproxen sodium 550 mg and acetaminophen/codeine 600/60 mg were the active comparators. Methods:A total of 201 patients with moderate to severe pain following surgical extraction of ≥2 third molars, of which at least the mandibular tooth was impacted, were randomly allocated to receive single oral doses of placebo (n = 50), etoricoxib 120 mg (n = 50), naproxen sodium 550 mg (n = 51), or acetaminophen/codeine 600/60 mg (n = 50). The endpoints included total pain relief over 8 hours (TOPAR8, primary end point), sum of pain intensity difference over 8 hours, patient’s global evaluation, onset, peak, and duration of analgesia. Results:Etoricoxib 120 mg had a significantly greater least squares (LS) mean TOPAR8 score than placebo (20.9 vs 5.4; P < 0.001) and acetaminophen/codeine 600/60 mg (20.9 vs 11.5; P < 0.001), and a similar LS mean TOPAR8 score to naproxen sodium 550 mg (20.9 vs 21.3). All three active treatments had rapid onset of analgesia, median time ~30 minutes. The duration of analgesic effect, defined as median time to rescue medication use, was >24 hours for etoricoxib, 20.8 hours for naproxen sodium, 3.6 hours for acetaminophen/codeine, and 1.6 hours for placebo. Discussion:Etoricoxib is a new COX-2 selective inhibitor under development for treatment of osteoarthritis, rheumatoid arthritis, and acute pain. In this study, etoricoxib 120 mg provided rapid and long-lasting pain relief to patients with moderate-to-severe postdental surgery pain. Etoricoxib was generally well tolerated.

Valdecoxib for treatment of primary dysmenorrhea. A randomized, double-blind comparison with placebo and naproxen.

OBJECTIVE: To compare the analgesic efficacy of valdecoxib with placebo and naproxen sodium for relieving menstrual cramping and pain due to primary dysmenorrhea.DESIGN: Single-center, double-blind study with a 4-period, 4-sequence crossover design. Patients assessed pain intensity and pain relief at regular intervals up to 12 hours following the initial dose.SETTING: Privately owned outpatient clinic.PATIENTS/PARTICIPANTS: One hundred twenty patient with moderate to severe menstrual cramping were randomized. Eighty-seven patients completed all treatment cycles.INTERVENTIONS: Valdecoxib 20 mg or 40 mg, naproxen sodium 550 mg, or placebo twice a day as required for ≤ 3 days in a single menstrual cycle.MEASUREMENTS AND MAIN RESULTS: Both doses of valdecoxib (20 and 40 mg) were comparable to naproxen sodium and superior to placebo at all time points assessed for each of the primary end points. Valdecoxib and naproxen sodium had comparable onset and duration of action. Although the study design allowed patients 2 doses per day, only 15% and 20% of patients in the valdecoxib 20 mg and valdecoxib 40 mg groups, respectively, required remedication within the first 12 hours. The incidence of adverse events was similar between active and placebo groups.CONCLUSION: Valdecoxib provided a fast onset of analgesic action, a level of efficacy similar to naproxen sodium, and a high level of patient satisfaction in the relief of menstrual pain due to primary dysmenorrhea. Valdecoxib was effective and well tolerated and thus appears to be a viable treatment for menstrual pain due to primary dysmenorrhea.

Analgesic Efficacy of Etoricoxib in Primary Dysmenorrhea: Results of a Randomized, Controlled Trial

Objective: To determine the efficacy of etoricoxib in the treatment of primary dysmenorrhea. Methods: Seventy-three women were randomly assigned to receive single oral doses of etoricoxib 120 mg, placebo, or naproxen sodium 550 mg at the onset of moderate to severe pain associated with menses. During 3 consecutive menstrual cycles in this double-blind, 3-period, crossover study, pain intensity and pain relief were assessed over the 24-hour period following dosing, and global ratings of therapy were made at 8 and 24 h after dosing. Tolerability was assessed by spontaneous reports of adverse experiences. Results: Etoricoxib 120 mg provided analgesic efficacy superior to placebo for the primary endpoint, total pain relief over 8 h (TOPAR8, p < 0.001), and for all secondary endpoints (p < 0.050). The analgesic effect of etoricoxib 120 mg over the first 8 h was similar to that of naproxen sodium 550 mg. All treatments were well tolerated. Conclusions: Etoricoxib 120 mg provided rapid and sustained analgesia that was superior to placebo and similar to that of naproxen sodium 550 mg.

Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations

Summary This article presents general considerations discussed at an IMMPACT consensus meeting regarding proof‐of‐concept (POC) clinical trials and major POC trial designs as well as their advantages and limitations when used to evaluate chronic pain treatments. ABSTRACT Proof‐of‐concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no‐go decision in a cost‐effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic–pharmacodynamic relationships, and minimization of missing data. Efficiency of single‐dose studies for treatments with rapid onset is discussed. The trade‐off between parallel‐group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N‐of‐1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.

Analgesic efficacy of preoperative parecoxib sodium in an orthopedic pain model.

The efficacy and safety of preoperative intravenous administration of parecoxib sodium, a novel parenteral prodrug of a cyclooxygenase-2 selective inhibitor, in treating postoperative pain resulting from bunionectomy were evaluated in 50 patients who were part of a larger cohort of orthopedic and podiatric patients. Following bunionectomy, the median time to rescue medication (survival analysis) was 4 hours 18 min (95% confidence interval, 3 hours 4 min to 4 hours 37 min) in the placebo group, 7 hours 5 min (95% confidence interval, 3 hours 20 min to >24 hours) in the 20-mg parecoxib sodium group, and 10 hours 43 min (95% confidence interval, 4 hours 42 min to 14 hours 7 min) in the 40-mg parecoxib sodium group (significant for 40-mg parecoxib sodium versus placebo). Four or more hours after surgery, the mean pain-intensity (categorical) score was significantly lower in both parecoxib sodium groups than in the placebo group. Preoperative administration of parecoxib sodium was well tolerated and significantly reduced postoperative pain in patients who had undergone bunionectomy.

A randomized controlled study comparing rofecoxib, diclofenac sodium, and placebo in post-bunionectomy pain.

SUMMARY Objective: The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery. Research design and methods: This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50 mg (N = 85), enteric-coated diclofenac sodium 100 mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50 mg or placebo (diclofenac patients switched to placebo) over study Days 2–5 (Part II). Patients rated their pain at 16 time points over the first 24 h. Primary endpoint was total pain relief over 8 h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2–5, with the focus on Days 2–3. Adverse experiences were recorded over Days 1–5. Results: For TOPAR8 scores, rofecoxib 50 mg was significantly more effective than placebo (9.5 vs. 3.7, p < 0.001) and diclofenac (9.5 vs. 5.0, p < 0.001). Onset of analgesia was more rapid with rofecoxib than placebo ( p = 0.003) and diclofenac ( p = 0.019); proportion of patients achieving onset within 4 h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p < 0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03 h vs. 4:02 h, p < 0.001 and 1:41 h vs. 4:02 h, p < 0.001). Rofecoxib patients used significantly less ( p < 0.001) supplemental analgesia than placebo patients over Days 2–3 (1.1 tablets/day vs. 2.1 tablets/day) and Days 2–5 (0.9 tablets/day vs. 1.8 tablets/day). No significant differences in adverse experiences between treatments were seen. Conclusion: Rofecoxib 50 mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50 mg was significantly more effective than diclofenac sodium 100 mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.

The Value of the Dental Impaction Pain Model in Drug Development

The modern version of the Dental Impaction Pain Model (DIPM) was developed in the mid-1970s. Since that time, several hundred studies have been conducted by numerous investigators. Today it is arguably the most utilized of all the acute pain models. Its popularity is due to the success rate of the studies, fast subject entry, and cost effectiveness. The surgical procedure is extremely standardized, and the surgery requires either minimal or no use of CNS depressant anesthetics. The methodology is similar to that utilized in other acute pain models; however, the DIPM is much more versatile than most other models. The model can be easily adapted to perform multiple-dose studies, pharmacokinetics/pharmacodynamics (PK/PD) correlations, preemptive interventions, and sleep-pain studies. A few investigators have even developed microdialysis techniques, wherein they insert probes into extraction sockets to collect exudates for measuring biochemical mediators of pain or drug levels at the site of injury. In many instances, an accomplished site can complete a study of several hundred subjects in approximately 3 months. There are studies in the literature that have incorporated up to six treatment arms in one study and clearly separated the drugs from each other. The exquisite assay sensitivity is due to the homogeneity of the study population, the predictable level and appropriate intensity of the postsurgical pain, and the minimizing of variability by using only one or two study centers. The DIPM has been employed to evaluate NSAIDs (both nonselective and selective Cox inhibitors), opioids and combination analgesics, as well as some investigational drugs with unique mechanisms of action. The model is particularly useful for proof-of-concept studies that require dose-ranging and profiling the time-effect curve for efficacy including onset, peak effect, and duration of analgesic activity.