1280 - Acute Pain Relief by a Proprietary, Nano-Formulated Lower-Dose Oral Indomethacin

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Roy D. Altman, UCLA, Los Angeles, CA, Stephen Daniels, Premier Research Group, Austin, TX and Garen Manvelian, Iroko Pharmaceuticals, Poway, CA
Presentation Number: 1280

Background/Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, are commonly prescribed for the relief of arthritic, musculoskeletal, and postoperative pain. Because there is a direct relation between dose of NSAID and adverse effects (AEs), there is a need to develop a formulation which safely provides fast onset of acute pain relief at a reduced dose of medication while decreasing the potential gastrointestinal AEs. This study evaluated the time to onset of analgesia of an investigational, proprietary, lower dose nano-formulated, oral indomethacin (nano-formulated indomethacin) compared with placebo, as well as a loading dose of celecoxib, in subjects with acute dental pain.

Method: This was a Phase 2, multicenter, randomized, double-blind, single-dose, parallel-group, placebo-controlled study. In total, 203 subjects were enrolled who were 18-50 years of age, had extraction of ≥2 third molars (at least 1 of which had to be a fully or partially impacted mandibular third molar), and experienced moderate to severe pain intensity (a score of ≥50 mm on a 100 mm Visual Analogue Scale [VAS]) ≤6 hours after surgery. Subjects assessed their baseline pain intensity (VAS) at Time 0 before receiving either nano-formulated indomethacin 20 mg or 40 mg, celecoxib 400 mg, or placebo. Efficacy variables included time to onset of analgesia and total pain relief. The Kaplan-Meier method was used to evaluate the treatment effect for each time to event endpoint. Time to onset of analgesia (measured as time to perceptible pain relief confirmed by meaningful pain relief) was based on data collected using the 2-stopwatch method.

Result: Data from the intent-to-treat population were included in the analysis. There was a statistically significant improvement in mean time to meaningful pain relief and mean time to peak pain relief for lower-dose nano-formulated indomethacin when compared with placebo (Table).

 

Parameter

Nano-formulated Indomethacin 20 mg Mean±SE

(N=50)

Nano-formulated Indomethacin 40 mg Mean±SE

(N=51)

Celecoxib  400 mg

Mean±SE

(N=51)

Placebo

Mean±SE

(N=51)

Mean Time to Meaningful Pain Relief (h)

2.4±0.25b

1.8±0.21a

2.6±0.40a

3.4±0.50

Mean Time to Peak Pain Relief (h)

3.4±0.39

2.6±0.30c

3.3±0.36

4.4±0.53

aP<0.001 compared with placebo

bP=0.08 compared with placebo

cP<0.05 compared with placebo

SE=standard error

Total pain relief over 8 hours (primary endpoint) for nano-formulated indomethacin was significantly (P<0.001) better compared with placebo (mean; 95% CI): 20mg (10.79; 2.66); 40mg (12.56; 2.64); placebo (3.02; 2.64). Tolerability data were comparable and there were no differences in treatment emergent adverse events between nano-formulated indomethacin 20 mg (38%; 19/50) or 40 mg (51%; 26/51), celecoxib (37.3%; 19/51), and placebo (56.9%; 29/51).

Conclusion: A lower dose, nano-formulated indomethacin demonstrated improved pain relief compared with placebo in this Phase 2 clinical trial, suggesting that use of this NSAID formulation may provide clinical benefit in the relief of acute arthritic/rheumatic and postoperative pain as a means of reducing AEs. Utilizing a lower dose, while maintaining efficacy, could result in an improved tolerability and safety profile and is in line with the FDA directive to use the lowest effective dose.


Keywords: clinical trials, nanomedicine, nonsteroidal antiinflammatory drugs (NSAIDs), pain and rheumatoid arthritis, treatment

Disclosure: R. D. Altman, None; S. Daniels, Consultant, 5 ; G. Manvelian, Consultant, 5 .