The Role of Oxytocin and Sex in Analgesic Placebo-Response: Exploratory Analysis from a Sham Randomized Clinical Trial in Chronic Back-Pain Patients

<b>Background:</b> 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. <b>Methods:</b> Chronic-back-pain patients (<i>n</i> = 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). <b>Results:</b> 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 (<i>p</i> = 0.024). Females exhibited greater pain reduction than males (<i>p</i> = 0.034). No interaction between the oxytocin change pattern and sex was observed. <b>Conclusions:</b> 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.