Placebo analgesia: Self-report measures and preliminary evidence of cortical dopamine release associated with placebo response

Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [(18)F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in Control and Placebo conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the Placebo PET visit, expected and recalled efficacy were highly correlated (ρ = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the Placebo condition (p < 0.001, uncorrected), and greater change in this measure was associated with higher levels of recalled analgesic efficacy (ρ = 0.58, p = 0.02). These preliminary findings underscore the need to consider how self-reported symptom improvement is assessed in clinical trials of analgesics and suggest that dopaminergic activity in the ventrolateral prefrontal cortex may promote recalled efficacy of placebo.