Objective: 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 (i.e. wiS.D.om tooth).
Methods: 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 500mg (n=39); or placebo (n=42). In a comparator study, 282 patients were randomized to AZD3582 500mg (n=78) or 750mg (n=83), rofecoxib 50mg (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.
Results: In the dose-finding study, 52% (126/242) were women; the mean (S.D.) age was 25.1 (4) years, mean weight was 69.0kg, and the mean (S.D.) body mass index (BMI) was 23.7 (3)kg/m2. In the comparator study, 58% (164/282) were women; the mean (S.D.) age was 27 (6.4) years, mean weight was 71kg, and mean (S.D.) BMI was 24.2 (3)kg/m2. 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 (0–8h)’ (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 115min for AZD3582 375mg, 66min for 750mg, 85min for 1500mg, 81min for 2250mg, and 162min for placebo (P=NS, P=0.003, P<0.003, and P<0.001, respectively). The median time to first rescue medication was 144min for placebo, and <50% of the subjects on any of the AZD3582 doses or naproxen took rescue medication within 8h after dosing. In the comparator study, AZD3582 750mg was superior to placebo in ‘time to rescue medicaton (0–24h)’ (HR [95% CI], 0.4 [0.3–0.6], P<0.001), ‘time to confirmed perceptible pain relief’ (2.1 [1.1–3.8], P=0.02), and MPID (11.9 [4.2–19.5], P=0.002). However, inferiority of AZD3582 to rofecoxib for MPID could not be excluded (tolerance limit of 10mm; P=NS for noninferiority testing). The median times to confirmed perceptible pain relief were 45min for AZD3582 500mg, 40min for 750mg, and 37min for rofecoxib. The median times to first rescue medication were 218min for AZD3582 500mg, 365min for 750mg, 635min for rofecoxib, and 90min for placebo. Overall, AZD3582 was well tolerated. However, an effect on orthostatic blood pressure could not be excluded because there seemed to be more subjects with dizziness and orthostatic blood pressure reduction who were administered AZD3582 ≥750mg. The proportions of patients with vertigo and decreased orthostatic blood pressure each group were as follows: AZD3582 500mg, 6%; AZD3582 750mg, 12%; rofecoxib, 3%; and placebo, 5%.
Conclusions: AZD3582 750mg had similar analgesic efficacy as equimolar doses of naproxen, but noninferiority to rofecoxib was not demonstrated. © 2006 Excerpta Medica, Inc.
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