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.

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 (ie, wisdom 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 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. RESULTS: 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/m2. 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/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 (0-8 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 minutes 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 to first rescue medication was 144 minutes for placebo, and <50% of the subjects on any of the AZD3582 doses or naproxen took rescue medication within 8 hours after dosing. In the comparator study, AZD3582 750 mg was superior to placebo in "time to rescue medication (0-24 hours)" (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 10 mm; P = NS for noninferiority testing). The median times to confirmed perceptible pain relief were 45 minutes for AZD3582 500 mg, 40 minutes for 750 mg, and 37 minutes for rofecoxib. The median times to first rescue medication were 218 minutes for AZD3582 500 mg, 365 minutes for 750 mg, 635 minutes for rofecoxib, and 90 minutes 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 > or =750 mg. The proportions of patients with vertigo and decreased orthostatic blood pressure each group were as follows: AZD3582 500 mg, 6%; AZD3582 750 mg, 12%; rofecoxib, 3%; and placebo, 5%. CONCLUSIONS: AZD3582 750 mg had similar analgesic efficacy as equimolar doses of naproxen, but noninferiority to rofecoxib was not demonstrated.

Continuous interscalene analgesia with ropivacaine 2 mg/ml after major shoulder surgery.

BACKGROUND: In this open, randomized study, the pharmacokinetics, clinical efficacy, and safety of a 48-h continuous interscalene infusion of 2 mg/ml ropivacaine for postoperative pain relief were investigated in patients undergoing open major shoulder surgery. METHODS: An initial interscalene block with 30 ml ropivacaine, 7.5 mg/ml (225 mg), was performed. After completion of interscalene block, all patients (n = 24) received general anesthesia, and 6 h after interscalene block, a 48-h continuous interscalene infusion of 12 or 18 mg/h using 2 mg/ml ropivacaine was started. Total and unbound plasma concentrations of ropivacaine and 2.6-pipecoloxylidide (PPX; a major active metabolite) were determined during and up to 6 h after the interscalene infusion. Postoperative pain at rest was assessed by a visual analog scale. Supplementary analgesics and adverse events were recorded. RESULTS: Plasma concentrations of total and unbound ropivacaine were proportional to the total dose. At the end of the interscalene infusion of 9 ml/h, the mean +/- SD plasma concentrations of total and unbound ropivacaine were 1.40 +/- 0.54 and 0.03 +/- 0.01 mg/l, respectively, and of total and unbound PPX were 0.70 +/- 0.38 and 0.30 +/- 0.20 mg/l, respectively. Plasma concentrations of unbound ropivacaine and unbound PPX, added together, remained well below threshold levels for systemic central nervous system toxicity. There were no significant differences between the groups for postoperative pain (median maximum of about 20 mm on the visual analog scale in both groups), analgesic consumption, or quality of pain relief assessed by the patient. No signs or symptoms of systemic local anesthetic toxicity were observed. CONCLUSION: A 48-h continuous interscalene infusion of 6 or 9 ml/h ropivacaine, 2 mg/ml, started 6 h after an initial interscalene block of 30 ml ropivacaine, 7.5 mg/ml, provided satisfactory postoperative pain relief after major shoulder surgery and was well tolerated. Unbound plasma concentrations of ropivacaine and PPX remained well below threshold levels for systemic central nervous toxicity.

Comparison of ropivacaine-fentanyl patient-controlled epidural analgesia with morphine intravenous patient-controlled analgesia for perioperative analgesia and recovery after open colon surgery.

STUDY OBJECTIVE: To compare the effects of ropivacaine-fentanyl patient-controlled epidural analgesia (PCEA) with morphine intravenous (IV) patient-controlled analgesia (PCA). DESIGN: Prospective, randomized, multicenter trial. SETTING: Five university-affiliated hospitals. PATIENTS: 41 patients undergoing colon surgery. INTERVENTION: Patients were randomized to receive either standardized combined epidural/general anesthesia followed by PCEA with ropivacaine 0.2% and fentanyl (2 microg/mL) or standardized general anesthesia followed by morphine IV PCA. All patients participated in a standardized postoperative clinical pathway. MEASUREMENTS AND MAIN RESULTS: Analgesia was assessed with visual analog scale (VAS) scores. Postoperative recovery was assessed by completion of prospectively defined discharge milestones and time until discharge. Statistical analyses included nonparametric and contingency table analyses. The PCEA group had better analgesia (> 50% reduction in pain scores, assessed both at rest and during a cough) for the first 3 days after surgery (p < 0.0,005). The PCEA group achieved discharge milestones approximately 36 hours faster (p < 0.002), but time until discharge was similar between groups. CONCLUSIONS: Ropivacaine-fentanyl PCEA provides superior analgesia, reduced opioid requirement, and more rapid recovery after colon surgery.