Altres ajuts: Dr Lopez-Sola was in part supported by the Serra Hunter faculty program at the University of Barcelona. This work was in part supported by grants R01AR074795 (M.L.S.), R01DA035484 (T.D.W.), R01DA035484 (T.D.W.), 3R01MH076136 (T.D.W.), R01EB026549 (T.D.W.), PSI2014-5352 (J.D.), and PSI2017-83777 (J.D.). The original studies were funded in part by the Neuroscience Centre of Excellence for Drug Discovery (CEDD)-GlaxoSmithKline (X71111961 and A3360529) and Bioibérica, S.A. (CS/IV-RMF-01). The clinical trials included in this study were approved by the local Ethics Committee (Clinical Research Ethical Committee-Institut Municipal d'Assistència Sanitària, Barcelona) and conducted in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki).

Supplemental Digital Content is Available in the Text. fMRI-based measures, validated for nociceptive pain, respond to acute osteoarthritis pain, are not sensitive to placebo, and are mild-to-moderately sensitive to naproxen. Many drug trials for chronic pain fail because of high placebo response rates in primary endpoints. Neurophysiological measures can help identify pain-linked pathophysiology and treatment mechanisms. They can also help guide early stop/go decisions, particularly if they respond to verum treatment but not placebo. The neurologic pain signature (NPS), an fMRI-based measure that tracks evoked pain in 40 published samples and is insensitive to placebo in healthy adults, provides a potentially useful neurophysiological measure linked to nociceptive pain. This study aims to validate the NPS in knee osteoarthritis (OA) patients and test the effects of naproxen on this signature. In 2 studies (50 patients, 64.6 years, 75% females), we (1) test the NPS and other control signatures related to negative emotion in knee OA pain patients; (2) test the effect of placebo treatments; and (3) test the effect of naproxen, a routinely prescribed nonsteroidal anti-inflammatory drug in OA. The NPS was activated during knee pain in OA (d = 1.51, P < 0.001) and did not respond to placebo (d = 0.12, P = 0.23). A single dose of naproxen reduced NPS responses (vs placebo, NPS d = 0.34, P = 0.03 and pronociceptive NPS component d = 0.38, P = 0.02). Naproxen effects were specific for the NPS and did not appear in other control signatures. This study provides preliminary evidence that fMRI-based measures, validated for nociceptive pain, respond to acute OA pain, do not appear sensitive to placebo, and are mild-to-moderately sensitive to naproxen.