Nonsteroidal Anti-inflammatory Drugs vs Cognitive Behavioral Therapy for Arthritis PainA Randomized Withdrawal Trial

Question  Is replacing meloxicam with placebo noninferior to continued meloxicam, and is engaging in a telephone-based cognitive behavioral therapy program noninferior to continuing meloxicam for patients with knee osteoarthritis?

Findings  In this multicenter randomized withdrawal trial, the pain scores of patients randomized to stop meloxicam were inferior at 4 weeks to the pain scores of patients who continued meloxicam; the pain scores of patients who engaged in cognitive behavioral therapy after placebo were also inferior to the pain scores of patients who continued meloxicam. However, the pain score differences between the 2 groups were small (less than the minimal clinically important difference), and there were no statistically significant differences in patients’ reported global impression of change or function.

Meaning  Among patients with knee osteoarthritis, placebo and cognitive behavioral therapy (after placebo) are inferior to meloxicam.

Importance  Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for knee osteoarthritis. However, they are associated with uncertain long-term clinical benefit and significant toxic effects.

Objective  To evaluate whether discontinuing NSAIDs and engaging in a telephone-based cognitive behavioral therapy (CBT) program is noninferior to continuing NSAIDs for patients with knee osteoarthritis.

Design, Setting, and Participants  The Stopping NSAIDs for Arthritis Pain multicenter randomized withdrawal trial was conducted for 364 patients taking NSAIDs for knee osteoarthritis pain on most days of the week for at least 3 months between September 1, 2013, and September 30, 2018. Analysis was performed on an intent-to-treat basis.

Interventions  Participants discontinued their current NSAID and took 15 mg per day of meloxicam daily during a 2-week run-in period. Those who remained eligible were randomized in a 1:1 ratio to receive meloxicam or placebo for 4 weeks (blinded phase 1). Participants receiving meloxicam then continued this medication for 10 weeks, while those receiving placebo participated in a 10-week CBT program (unblinded phase 2).

Main Outcomes and Measures  The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 4 weeks with the noninferiority margin set at 1. Secondary outcomes included the area under the curve of the pain score after 4 weeks as well as the WOMAC pain score, area under the curve of the pain score, WOMAC disability score, and global impression of change after treatment at 14 weeks.

Results  A total of 180 participants (161 men; mean [SD] age, 58. 2 [11.8] years) were randomized to receive placebo followed by CBT, and a total of 184 participants (154 men; mean [SD] age, 58.5 [10.0] years) were randomized to receive meloxicam. After adjustment for baseline pain and study site, the estimated mean difference in WOMAC pain score between the placebo and meloxicam groups after 4 weeks was 1.4 (95% CI, 0.8-2.0; noninferiority test P = .92). At week 14, the adjusted mean difference in WOMAC pain score between the placebo (followed by CBT) and meloxicam groups was 0.8 (95% CI, 0.2-1.4; noninferiority P = .28). There was no statistically significant difference in the global impression of change (mean difference in scores, –0.2; 95% CI, –0.4 to 0.1; P = .15) or lower extremity disability (mean difference in scores, 0.9; 95% CI, –1.4 to 3.2; P = .45) between the 2 groups after 14 weeks.

Conclusions and Relevance  Among patients with knee osteoarthritis, placebo and CBT (after placebo) are inferior to meloxicam. However, the WOMAC pain score differences between the 2 groups were small, and there were no statistically significant differences in participants’ global impression of change or function after 14 weeks.

Trial Registration  ClinicalTrials.gov Identifier: NCT01799213