Predicting placebo analgesia responses in clinical trials: where to look next? A meta-analysis of individual patient data

Estimating the magnitude of placebo responses across pharmacological and nonpharmacological trials is important for understanding their influence on trial outcomes. Yet, the extent to which more intense placebo interventions like sham acupuncture yield larger analgesic responses than placebo pills, and the factors predicting these responses, remain unclear. This meta-analysis investigated the magnitude and predictors of placebo analgesia responses in pharmacological vs acupuncture trials. Analyses included individual patient data from the placebo arm of 11 randomized controlled trials (RCTs): 9 pharmacological RCTs using placebo pills (N = 2021) and 2 acupuncture RCTs using sham acupuncture (N = 747). All trials were conducted in patients with chronic nociceptive pain (osteoarthritis, N = 2068; low back pain, N = 700). The placebo response was calculated as the change in pain intensity (0-100) between baseline and week 12. A random effects model demonstrated that placebo pills and patients with osteoarthritis exhibited smaller placebo responses than sham acupuncture and patients with low back pain (both P < 0.001, marginal effects). A mixed effects model showed that route of administration interacted significantly with baseline pain, premature termination, and the presence of adverse events. Together, predictors explained 20% to 25% of the individual variance in placebo responses, whereas 75% to 80% remained unaccounted for. In summary, sham acupuncture accounted for slightly larger placebo responses than placebo pills. Since basic trial and patient parameters explained only a small portion of this variability, we might need to start considering the patient's perception of the treatment-including cognition and emotions-to better predict placebo analgesia responses.