A deeper look at pain variability and its relationship with the placebo response: results from a randomized, double-blind, placebo-controlled clinical trial of naproxen in osteoarthritis of the knee

Abstract

Previous studies have shown a robust correlation between variability of clinical pain scores and responsiveness to placebo (but not active drug) in pain studies, but explanations for these relationships are lacking. We investigated this further by assessing relationship between the Focused Analgesia Selection Test (FAST), a psychophysical method that quantifies pain reporting variability in response to experimental stimuli, variability of daily clinical pain scores as captured using diary, and response to treatment in the context of a randomized controlled crossover trial of naproxen vs placebo in knee osteoarthritis. Evoked pain using the Staircase-Evoked Pain Procedure served as the primary efficacy endpoint. Variability of daily pain scores and the FAST were assessed at baseline. Fifty-five subjects completed the study and were included in the analyses. Our results indicated a statistically significant, moderate linear relationship between variability of clinical and experimental pain reports (r = −0.416, P = 0.004). Both correlated with the placebo response (r = 0.393, P = 0.004; r =−0.371, P = 0.009; respectively), but only the FAST predicted the treatment difference between naproxen and placebo, as demonstrated both in a regression model (P = 0.002, Beta = 0.456, t = 3.342) and in a receiver operating characteristic curve (0.721) analysis. Our results extend previous findings to include a correlation between experimental pain variability and the placebo response and suggest that experimental pain variability is a better predictor of patients who respond preferentially to drug over placebo. A theoretical model unifying these observations is proposed, and practical implications are discussed.

The Protective Effect of New Carnosine-Hyaluronic Acid Conjugate on the Inflammation and Cartilage Degradation in the Experimental Model of Osteoarthritis

“…Furthermore this study has demonstrated that FidHycarn using two safe products: carnosine and HA has a bio-pharmacological effect comparable to the treatment with naproxen (a standard treatment for OA but with proven side effects) [53], at the clinical dose per kg, for almost all the parameters assessed, without significant statistical differences. In conclusion, the results obtained demonstrate for the first time in an animal model of osteoarthritis the effectiveness of oral administration of the conjugate FidHycarn compared to the administration of the individual components.…”

Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice

“…Patients without sensory precision training had significantly higher placebo responses 134. A subsequent replication study in patients with knee osteoarthritis (n=55) found analogous results 135…”

The relation between the placebo response, observed treatment effect, and failure to meet primary endpoint: A systematic review of clinical trials of preventative pharmacological migraine treatments

“…There are many factors that can contribute to a high placebo response such as the placebo effect itself, natural improvement in the population, poor research or study design, and regression to the mean (1). For neurological disorders such as neuropathic pain and Parkinson’s disease, a high placebo response has indeed been shown to have an impact on the separation between placebo and active treatment (2–4).…”