The true size of placebo analgesia: Concordant neural and behavioural measures of placebo analgesia during experimental acute pain

Placebo analgesia refers to the reduction of pain following the administration of an inactive treatment. While most clinical trials compare a drug treatment against a placebo to determine the efficacy of the analgesic, most experimental studies of placebo analgesia do not include a real analgesic condition. A direct comparison of placebo against a real analgesic can inform us about the true size of the placebo effect. To this end, we aimed to provide a robust estimate of placebo analgesia by contrasting the effect of pain relief expectation from an inert cream (vaseline) against a real topical analgesic agent (lidocaine) applied on two different limbs and their respective control conditions. Pain reports and electroencephalography (EEG) responses triggered by laser nociceptive stimulation were collected. Forty typical healthy adults were enrolled in a double-blind randomized within-subject study where a standard placebo induction script of verbal suggestions in a sham medical setting was used to enhance the expectation on treatment outcome. In line with the earliest studies of placebo analgesia, majority (30 of 40) of participants was placebo responders, i.e. they reported lower pain to the placebo treatment. Placebo responders reported low pain and displayed low laser evoked potentials (LEPs) amplitude for both the analgesic and placebo treatment limbs compared to the respective control limbs. Placebo analgesia correlated positively with the amplitude of the LEPs, thus establishing convergent validity of the findings. This study provides a robust estimate of the neural and behavioural measures of placebo analgesia, in comparison to a real analgesic. These estimates can help inform the quantitative criteria for similar neural and behavioural measures in assessing the effectiveness of a real drug in placebo controlled trials.