Analgesic efficacy of the cyclooxygenase-inhibiting nitric oxide donor AZD3582 in postoperative dental pain: Comparison with naproxen and rofecoxib in two randomized, double-blind, placebo-controlled studies

• Published in: Clinical therapeutics 2006-09, Vol.28 (9), p.1279-1295
• Main Authors: Michael Hill, C., Sindet-Pederson, Steen, Seymour, Robin A., Hawkesford, John E., Coulthard, Paul, Lamey, Philip John, Gerry Cowan, C., Wickens, Mark, Jeppsson, Lennart, Dean, Andrew D.P., Svensson, Ola
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; analgesic; Analgesics; AZD3582; Biological and medical sciences; Bone surgery; Clinical trials; Cyclooxygenase Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - therapeutic use; Dental surgery; Dentistry; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastroenterology; Humans; Lactones - administration & dosage; Lactones - therapeutic use; Male; Mandible - surgery; Maxillofacial surgery; Medical sciences; Middle Aged; Molar, Third - surgery; Morphine; Naphthalenes - administration & dosage; Naphthalenes - therapeutic use; naproxen; Naproxen - administration & dosage; Naproxen - therapeutic use; Nitric oxide; Nonsteroidal anti-inflammatory drugs; oral surgery; Pain; Pain Measurement; Pain, Postoperative - drug therapy; Pain, Postoperative - etiology; Pharmacology. Drug treatments; postoperative dental pain; rofecoxib; Sodium; Sulfones - administration & dosage; Sulfones - therapeutic use; Tooth Extraction; Treatment Outcome
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2006.09.015

This study assessed the analgesic efficacy of single doses of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (AZD3582) in acute postoperative dental pain after the removal of an impacted mandibular third molar (ie, wisdom tooth). Two randomized, placebo-controlled, double-blind studies were performed. In a dose-finding study, 242 patients were randomized to AZD3582 375, 750, 1500, or 2250 mg (n = 41, 37, 42, and 41, respectively); naproxen 500 mg (n = 39); or placebo (n = 42). In a comparator study, 282 patients were randomized to AZD3582 500 mg (n = 78) or 750 mg (n = 83), rofecoxib 50 mg (n = 80), or placebo (n = 41). Primary outcomes included time to rescue medication, time to pain relief, and mean pain intensity difference (MPID), as well as safety profile. Pain was rated on a visual analog scale. In the dose-finding study, 52% (126/242) were women; the mean (SD) age was 25.1 (4) years, mean weight was 69.0 kg, and the mean (SD) body mass index (BMI) was 23.7 (3) kg/m 2. In the comparator study, 58% (164/282) were women; the mean (SD) age was 27 (6.4) years, mean weight was 71 kg, and mean (SD) BMI was 24.2 (3) kg/m 2. In the dose-finding study, the AZD3582 750-, 1500-, and 2250-mg groups were superior to placebo in the primary variables “time to rescue medication (0–8 hours)” (hazard ratios [HRs] [95% CIs], 0.17 [0.07–0.42], P < 0.003; 0.23 [0.11–0.50], P < 0.001; and 0.15 [0.06–0.36], P < 0.001, respectively), “time to meaningful pain relief” (HRs [95% CIs], 3.42 [1.87–6.25], P < 0.003; 2.49 [1.37–4.50], P < 0.003; and 3.07 [1.70–5.55], P < 0.001, respectively), and MPID (analysis of covariance [ANCOVA] least squares mean [LSM] differences [95% CIs], 25.8 [17.3–34.4], P < 0.003; 20.4 [12.1–28.7], P < 0.003; and 29.3 [20.9–37.6], P < 0.001, respectively). AZD3582 and naproxen did not show any statistically significant differences for the 3 primary variables, except that naproxen was superior to the AZD3582 375-mg dose for the variables time to meaningful pain relief (HR difference, 0.48 [95% CI, 0.29–0.78], P < 0.004) and MPID (difference in ANCOVA LSM, -10.2, [95% CI, -18.2 to -2.2], P < 0.012). The median times to meaningful pain relief were 115 minutes for AZD3582 375 mg, 66 minutes for 750 mg, 85 min utes for 1500 mg, 81 minutes for 2250 mg, and 162 minutes for placebo ( P = NS, P = 0.003, P < 0.003, and P < 0.001, respectively). The median time tofirst res cue medication was 144 minutes for placebo, and