Onset and durability of pain relief in knee osteoarthritis: Pooled results from two placebo trials of naproxen/esomeprazole combination and celecoxib

Abstract

Objective. To further characterize time-to-first pain relief, effect size, correlations between various outcome measures and durability of relief for single-tablet naproxen 500 mg/esomeprazole 20 mg (NAP/ESO) given twice daily and celecoxib (CEL) (200 mg) given once daily versus placebo in knee osteoarthritis (OA). Methods. Unpublished data from two double-blind, double-dummy, placebo-controlled trials in which patients aged ≥50 years with knee OA were randomized to NAP/ESO (n = 487), CEL (n = 486) or placebo (n = 246) were pooled (NCT00664560 and NCT00665431). Acute response endpoints: 1) Time to first significant pain response, 2) Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain subscale and 3) American Pain Society Patient Outcome Questionnaire (APS-POQ) scores. Sustainability endpoints: 1) Routine Assessment of Patient Index Data (RAPID3) and 2) WOMAC Stiffness, Pain and Total scores; and Patient Global Assessment (PGA) at 6 and 12 weeks. Effect sizes for all measures were calculated. Rescue pain medication use also was analyzed, as was the correlation of WOMAC to RAPID3. Results. NAP/ESO produced statistically significant decreases in WOMAC Pain on Days 2–7 and at Weeks 6 and 12 (all p < 0.05); most APS-POQ pain assessments with NAP/ESO were significantly improved on Days 2–7 compared with placebo (all p < 0.05). A good or excellent response occurred in a median of 6 days. RAPID3 and WOMAC total/stiffness/function/PGA scores decreased significantly at Weeks 6 and 12 (all p < 0.05). Placebo-adjusted WOMAC pain effect sizes were 0.44, 0.34 and 0.25 at Day 7, week 6 and week 12, respectively. RAPID3 to WOMAC total and WOMAC pain to RAPID3: Pain scores were highly correlated at 6 and 12 weeks (correlation coefficients >0.80). No significant differences in overall responses were found between CEL and NAP/ESO. Conclusion. Naproxen/esomeprazole produced a significant absolute moderate early pain response, which was maintained for 12 weeks. RAPID3 was found to be highly correlated with the typical OA measure (WOMAC) and might be a useful clinical tool for measuring NSAID response. NCT00664560: https://clinicaltrials.gov/ct2/show/NCT00664560, NCT00665431: https://www.clinicaltrials.gov/ct2/show/NCT00665431.

Keywords:

• Celecoxib
• effect size
• naproxen combination
• pain
• Routine Assessment of Patient Index Data
• Western Ontario and McMaster Osteoarthritis Index

Acknowledgments

The authors would like to thank Jana Steinmetz of Premier Research, Inc, Naperville, IL, and Ying Zhang of POZEN, Inc, Chapel Hill, NC, for statistical support. Medical writing services were provided by Cathryn M. Carter, MS, and Tonya Goodman, of Arbor Communications, Inc; this support was funded by Horizon Pharma USA, Inc.

Declaration of interest

POZEN Inc. sponsored the original studies. The pooled analysis was funded by Horizon Pharma USA, Inc. John G Fort is an employee of POZEN, Inc and current stock and stock option holder. Jeffrey D Kent and Amy Y Grahn are employees of Horizon Pharma USA, Inc and current stock and stock option holders. Robert J Holt has served as a consultant for POZEN, Inc and Horizon Pharma USA, Inc. Alfonso E Bello has been a consultant for Horizon Pharma USA, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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