Background Indomethacin is used to treat acute gouty arthritis and other acute pain conditions, but similar to other NSAIDs, is associated with dose-related gastrointestinal, cardiovascular, and renal complications. International health authorities recommend that NSAIDs be used at the lowest effective dose. To deliver effective pain relief with lower systemic exposure than commercially available NSAIDs, Iroko Pharmaceuticals, LLC is developing an investigational, lower-dose SoluMatrix® indomethacin drug product manufactured using SoluMatrix Fine Particle Technology™ that contains submicron indomethacin drug particles allowing for faster dissolution. In a phase 1 pharmacokinetic study, lower dose submicron indomethacin 40 mg demonstrated faster absorption (tmax), comparable maximum plasma concentrations (Cmax), and lower overall extent of exposure (AUC0–∞) compared with conventional indomethacin immediate-release capsules 50 mg under fasting conditions.
Objectives To evaluate the efficacy of lower-dose submicron indomethacin compared with placebo in two phase 3 studies in postsurgical patients.
Methods Two phase 3, multicenter, double-blind studies enrolled patients aged 18–68 years with moderate-to-severe acute pain (≥40 mm/100 mm by Visual Analog Scale) following bunionectomy. Patients were randomized to receive lower-dose submicron indomethacin 40 mg TID, 40 mg BID, 20 mg TID, or placebo. One study included a treatment group of celecoxib 400-mg loading dose followed by 200 mg BID. The efficacy parameters for both studies included the overall (summed) pain intensity difference over 0-48 h (SPID-48) following the first dose of study medication and pain intensity differences (PID) at each scheduled assessment.
Results In total, 835 patients were enrolled: 462 in study 1 and 373 in study 2. In study 1, the lower-dose submicron indomethacin 40 mg TID (509.6±91.9;P<0.001), 40 mg BID (328.0±92.9;P=0.046), and 20 mg TID (380.5±92.9;P=0.017) groups experienced significantly greater reductions in overall pain intensity over 0–48 h (LS mean SPID-48 ± SE) compared with placebo (67.8±91.4). While the celecoxib 400 mg loading dose followed by 200 mg BID (279.4±91.9;P=0.103) group experienced some pain relief, SPID-48 was not significant compared with placebo. In study 2, lower-dose submicron indomethacin 40 mg TID (598.5±105.7;P=0.034) and BID (623.0±106.2;P=0.023) provided significantly greater reductions in pain intensity over 0–48 h compared with placebo (280.9±105.8). Lower-dose submicron indomethacin 20 mg TID (342.8±106.8;P=0.680) did not achieve significant reductions in overall pain intensity over 0–48 h compared with placebo, likely due to the high level of analgesia observed in the placebo group. In study 1, analgesia was apparent based on PID in the lower-dose submicron indomethacin 40 mg TID (2.9;P=0.309) and 40 mg BID (2.6;P=0.316) groups compared with placebo (0.2) 30 min after dosing, but was not statistically significant. In study 2, analgesia was present at 15 min after dosing in patients treated with lower-dose submicron indomethacin 40 mg BID (2.2;P=0.451) compared with placebo (0.5).
Conclusions Lower-dose submicron indomethacin provided effective analgesia in two phase 3 studies in patients with acute pain following bunionectomy and represents a potentially promising treatment option for patients with acute pain.
Disclosure of Interest : R. Altman Consultant for: Pfizer, Teva Pharmaceutical Industries Ltd., Petah Tikva, Oletec, Novartis, Johnson & Johnson, Iroko Pharmaceuticals, LLC, Ferring Pharmaceuticals, Speakers bureau: Ferring Pharmaceuticals, A. Gibofsky Shareholder of: GlaxoSmithKline plc, Bristol-Myers Squibb, Amgen, Pfizer, AbbVie, and Johnson & Johnson, Consultant for: Takeda, Amgen, AbbVie, Genentech, Horizon, UCB, and Iroko Pharmaceuticals, LLC, D. Parenti Employee of: Iroko Pharmaceuticals, LLC, C. Young Employee of: Iroko Pharmaceuticals, LLC