Background: Several studies suggest that exogenous oxytocin nasal spray may enhance placebo analgesia in healthy volunteers and experimental pain models, although the findings remain mixed. The oxytocin placebo hypothesis suggests that increased oxytocin levels trigger a cascade of brain processes that boost positive expectations and augment the placebo response. Since endogenous oxytocin secretion has been found to increase during positive interactions, we hypothesized that changes in endogenous oxytocin levels will affect placebo analgesia in chronic-back-pain patients. Given the role sex has in both placebo analgesia and oxytocin secretion, we hypothesized that the response magnitude will differ by sex. Methods: Chronic-back-pain patients (n = 112) were prospectively recruited and received placebo injections. The placebo response was calculated as the change in the back-pain Visual Analog Score (VAS), and changes between pre- and post-injection salivary oxytocin levels were measured. The effect of sex and changes in oxytocin levels on pain reduction was calculated using two-way analysis of variance (ANCOVA). Results: Oxytocin levels decreased in 62.5% of participants and increased in 37.5%. Increased oxytocin levels were associated with greater pain reduction than decreased oxytocin levels (p = 0.024). Females exhibited greater pain reduction than males (p = 0.034). No interaction between the oxytocin change pattern and sex was observed. Conclusions: This study demonstrates that following a placebo injection, patients suffering from chronic back pain, who exhibited an increase in endogenous oxytocin levels, showed a higher placebo response. Females had a greater placebo response, but this was not associated with an endogenous oxytocin change. These results provide initial support for the oxytocin placebo hypothesis.

Individuals with chronic pain such as fibromyalgia (FM) are often experiencing disappointing outcomes from clinical therapies, which theoretically should condition them to experience low placebo analgesia. However, no consistent differences in the placebo effect were found between healthy controls (HC) and chronic pain patients. This study examined the expectations, conditioning, and placebo effect in HC and FM, and the relationships between these factors in both groups. Female HC and FM patients were recruited, provided demographic and clinical information and underwent the experimental placebo paradigm. This paradigm has the advantage of measuring expectations (baseline, reinforced, and after placebo), conditioning, and placebo effect. Mixed factorial ANCOVAs, correlational analysis, stepwise and moderation regression analysis were employed. Thirty-seven HC and 32 FM patients participated. Three Mixed factorial ANCOVAs showed no main effects of group or interactions for expectations (p = .692), conditioning (p = .357), or placebo effect (p = .819). Reinforced expectations predicted the conditioning strength (r = .48, p = .008) and placebo effect (r = .44, p = .014) in HC but not in FM participants. In FM, duration of pain predicted the reinforced expectations (r = -.38, p = .035) and moderated the prediction of the placebo effect by the conditioning strength (b = .04, p = .011). While the classical placebo theorem is supported in healthy controls, with conditioning influencing expectations, which in turn predict the placebo effect, these associations are not observed in fibromyalgia, where prior clinical experience plays a more significant role. These findings underscore the impact of previous negative clinical experiences on the placebo effect and, possibly, on responses to effective treatments.

Introduction: Within-subject variability (WSV) of pain intensity reports has been shown to predict the placebo response. The focused analgesia selection test (FAST), which allows to experimentally assess WSV of pain reports, has been used as a screening tool to identify participants who are likely to have a strong placebo response in drug-development clinical trials. Yet, the reliability of FAST has not been reported. Objectives: To assess test–retest and interrater reliability of the FAST outcomes. To mimic pharma-sponsored clinical trials, we enlisted inexperienced assessors who underwent limited training. Methods: Healthy volunteers performed the FAST twice within a week and were randomly assigned to either the test–retest group or the interrater group. T-tests, partial Pearson correlations, intraclass correlations (ICC), and Bland–Altman plots were generated to assess FAST outcomes' reliability. Results: Sixty-three participants completed the study and were assigned to the test–retest (N = 33) or interrater (N = 30) arms. No statistically significant differences in the FAST outcomes were detected between the 2 sessions, except for the FAST covariance (FAST CoV) in the interrater assessment (P = 0.009). Test–retest reliabilities of the FAST-main outcomes were r = 0.461, ICC = 0.385 for the FAST R ² and r = 0.605, ICC = 0.539 for the FAST ICC and in the interrater cohort, they were FAST R ²: r = 0.321, ICC = 0.337 and FAST ICC: r = 0.355, ICC = 0.330. Conclusion: Using inexperienced assessors, the FAST outcomes test–retest ranged from moderate to strong, whereas the interrater reliability ranged from weak to poor. These results highlight the importance of adequately training study staff members before using this tool in multicentre clinical trials.

Introduction: Communication between medical staff and patients about treatment efficacy elicits expectations of benefit and improves treatment outcomes. While demonstrated in multiple studies via different research methodologies, uniform communication protocols have not been adopted in clinical practice. Here, we summarize the results of two sister studies aimed at bridging this gap. Methods: Women undergoing C-section (study 1, randomized controlled trial) and patients undergoing general or otolaryngologic surgeries (study 2, control group design) were recruited and assigned to the “regular communication” (RC) or “enhanced communication” (EC) arms. The EC arm received positive information about treatment, while the RC arm received no such information. In both studies, the primary outcome was change in pain intensity; in study 2, an additional outcome was morphine consumption. Results: Eighty women successfully completed study 1, and 102 patients successfully completed study 2. In both studies, significant time*group interactions were observed (p < 0.001). The analgesic effect was virtually twice as large in the EC arm compared to the RC arm. In study 2, in the last two timepoints of assessment, participants in the EC arm also consumed fewer doses of opioids than participants in the RC arm (p < 0.001). No significant differences were found in vital signs. Conclusions: We provide ecological evidence that positive information about treatment significantly decreases pain and opioid consumption during routine clinical care. This study and others could encourage healthcare providers to harness the powerful effects of patients’ expectations of benefit to improve analgesics outcomes and, potentially, the outcomes of other symptoms.