The neurologic pain signature responds to nonsteroidal anti-inflammatory treatment vs placebo in knee osteoarthritis

Marina López-Solà, Jesus Pujol, Jordi Monfort, Joan Deus, Laura Blanco-Hinojo, Ben J Harrison, Tor D Wager, Marina López-Solà, Jesus Pujol, Jordi Monfort, Joan Deus, Laura Blanco-Hinojo, Ben J Harrison, Tor D Wager

Abstract

Introduction: 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.

Objectives: This study aims to validate the NPS in knee osteoarthritis (OA) patients and test the effects of naproxen on this signature.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Chronic pain; NSAID; Neurologic pain signature; Osteoarthritis; Placebo; fMRI.

Conflict of interest statement

The authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Figures

Figure 1.
Figure 1.
Study designs and summary of methodological approach. (A) Study designs for study 1 and study 2. The 23 patients in study 1 experienced 3 different visits in separate days: One with no treatment, one after a placebo pill, and a third after a naproxen pill (see Methods and supplementary materials for full description, http://links.lww.com/PR9/A148). The 27 patients in study 2 underwent a first visit (basal, no treatment) and a second visit (final, placebo) after receiving placebo treatment (pills) for 120 days. One contrast image representing [pain activation period (1) > rest (−1)] was obtained for each patient and each condition. (B) Summary of the methodology. Each individual contrast image was multiplied by each of the preselected, validated pain-related (NPSp, NPS, and SIIPS1) and control (emotion related, PINES and Distress) signatures (multivariate brain weighted maps that had been previously identified to maximally predict different aspects of pain or emotion in previous studies, see referenced articles). This yields one pattern response score per person per condition. NPSp, pronociceptive neurologic pain signature; NPS, neurologic pain signature; SIIPPS1, Stimulus Intensity–Independent Pain Signature 1.
Figure 2.
Figure 2.
Pain-related multivariate signatures (previously published and validated) and signature response (dot-product pattern expression) for each signature, for each study and condition. The top row shows a graphic representation of the signature brain weighted maps for reference (and the original publications): the NPSp, the NPS, and the SIIPS1. Individual dots represent signature responses (dot-product pattern expression) for each OA patient in each study (2 separate cohorts, 23 patients in study 1 and 27 patients in study 2). Bars around the mean represent within-person SE bars (Loftus and Masson, 1994). ***P < 0.001, **P < 0.01, *P < 0.05. NPSp, pronociceptive neurologic pain signature; NPS, neurologic pain signature; SIIPPS, Stimulus Intensity–Independent Pain Signature 1.
Figure 3.
Figure 3.
Pain-related multivariate signatures (previously published and validated) and signature response (dot-product pattern expression) for each signature, for each study and condition. The top row shows a graphic representation of the signature brain weighted maps for reference (and the original publications): the PINES (Picture-Induced Negative Emotion Signature) and Distress Signature. Individual dots represent signature responses (dot-product pattern expression) for each OA patient in each study (2 separate cohorts, 23 patients in study 1 and 27 patients in study 2). Bars around the mean represent within-person SE bars (Loftus and Masson, 1994). *P < 0.05. OA, osteoarthritis.

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