This short-term study established that lumiracoxib, a novel COX-2 selective inhibitor, provides rapid and effective analgesia in patients with OA of the knee. The primary efficacy variable (mean PID 3–5 hours after dose) was similar to those used in other single-dose studies of COX-2 selective inhibitors in acute pain [26
] or in patients with OA flare [27
]. Celecoxib was chosen as the active comparator because of its established analgesic efficacy in patients with OA of the knee [28
Previous studies have shown that lumiracoxib provides significant pain relief over 13 weeks of treatment in patients with OA compared with placebo [30
]. In the present study we found that the first dose of lumiracoxib 400 mg decreased OA pain intensity (100 mm VAS) 3–5 hours after dose by 19.8 mm (P
= 0.004, versus placebo) compared with a mean decrease of 16.8 mm (P
= 0.069, versus placebo) with celecoxib 200 mg and 13.4 mm with placebo. Lumiracoxib was noninferior but not significantly superior to celecoxib in this analysis 3–5 hours after dose. These findings are consistent with earlier pharmacodynamic studies with lumiracoxib, which found the difference from baseline in mean VAS scores at 4 hours after dosing to be >20 mm with lumiracoxib 400 mg compared with <5 mm in placebo-treated patients [32
]. The results reported here are similar to findings with other COX-2 selective inhibitors, where the speed of onset of analgesia was studied in an OA population meeting OA flare criteria [27
]. At 3 hours after the dose, the mean decrease in OA pain intensity (100 mm VAS) was 21.7 mm with valdecoxib 10 mg and 19.8 mm with rofecoxib 25 mg, as compared with 15.5 mm with placebo (P
< 0.01). In addition, it has been reported that a 30–33% decrease in VAS pain scores represents a clinically meaningful change in either acute or chronic pain [33
]. For lumiracoxib 400 mg, a 30% decrease from actual pain at baseline was observed at the 3–5 hour post-dose assessment, suggesting that this change in pain intensity was clinically relevant.
The primary objective of the study was to examine the single-dose onset of analgesia with lumiracoxib. As such, a dose of lumiracoxib appropriate for acute use (400 mg) was used. Previous studies with this dose of lumiracoxib in acute pain have shown that it provides rapid and effective analgesia [35
]. The recommended chronic dose of lumiracoxib is 100 mg daily. In order for the active comparison to be relevant, a dose of celecoxib considered to be appropriate for acute pain was chosen (200 mg twice daily) [22
]. (The recommended dose of celecoxib in OA is 200 mg daily, administered as a single dose or as 100 mg twice daily [22
Both lumiracoxib and celecoxib had statistically significant efficacy compared with placebo in terms of secondary efficacy variables assessed during the multiple-dose assessment period, including APID, AVPID, WPID and extent of pain relief. The significant treatment–placebo differences in actual pain intensity (100 mm VAS) at study end (10.7 mm for lumiracoxib 400 mg once daily, P
= 0.001; 8.7 mm for celecoxib 200 mg twice daily, P
= 0.005) were comparable with those previously reported after 13 weeks of treatment (8.8 mm for lumiracoxib 400 mg once daily; 6.3 mm for celecoxib 200 mg once daily) [31
]. At study end, no significant differences were observed between active treatments in terms of APID. Substantially more patients in the lumiracoxib group assessed treatment effect as 'excellent' or 'good' at study end compared with those who received celecoxib (58% and 49%, respectively). Interestingly, only around 25% of placebo recipients rated treatment as 'poor' at the end of the study, despite a progressive increase in APID during treatment. This 'placebo effect' is not unique to the treatment of patients with joint disorders [38
] and is perhaps attributable to psychological mechanisms such as an awareness of being closely observed and active compliance with the presumed wishes of researchers. It is notable, however, that against this background lumiracoxib maintained significant superiority in terms of analgesic efficacy.
Patients received celecoxib 200 mg in the morning and evening, whereas lumiracoxib was given in the morning only, with a lumiracoxib-matched placebo administered in the evening. The multiple-dose actual PID scores for lumiracoxib over the 7-day treatment period show that the analgesic effect of lumiracoxib is maintained over a 24-hour period and therefore supports once-daily administration.
Evaluation of WOMAC™ subscales in the study allowed assessment of the effect of treatment on aspects of patients' daily lives relating to their condition, including pain, stiffness and the ability to perform daily activities. Overall, both lumiracoxib and celecoxib were associated with significantly lower pain and stiffness WOMAC™ subscale scores than placebo at study end. This is of particular significance for patients with knee OA, whose mobility and quality of life can be severely impaired [39
]. Treatment–placebo differences in the WOMAC™ total score at 7 days (8.9 for lumiracoxib 400 mg once daily; 4.8 for celecoxib 200 mg twice daily) were comparable with those seen in longer 13-week studies with lumiracoxib and celecoxib (7.5 for lumiracoxib 400 mg once daily; 6.0 for celecoxib 200 mg once daily) [31
]. It has been suggested that the minimal difference perceived (MDP) clinically from baseline in WOMAC™ DPDA score should be the minimal difference that is perceived by 75% of patients (MDP75), and a recent study of 1354 patients reported the MDP75 for the WOMAC™ DPDA subscale to be 5.2 [40
]. In this study, the change from baseline in the DPDA subscale score was 15.4 for lumiracoxib 400 mg once daily compared with 12.3 for celecoxib 200 mg twice daily. This suggests that lumiracoxib provided clinically meaningful improvements in the ability of patients to perform daily activities during this 7-day study.
Lumiracoxib was well tolerated in this short study. The incidence of adverse events was comparable between all three groups. Previous studies of lumiracoxib tolerability over 13 weeks of treatment have found that lumiracoxib 200 mg or 400 mg daily has gastrointestinal tolerability that is superior to that of traditional NSAIDs including diclofenac, ibuprofen and naproxen [41