Investigating dose-dependent effects of placebo analgesia: A psychophysiological approach Yoshio Nakamura ⇑ , Gary W. Donaldson, Renee Kuhn, David H. Bradshaw, Robert C. Jacobson, C. Richard Chapman Department of Anesthesiology, Pain Research Center, Utah Center for Exploring Mind-Body Interactions (UCEMBI), University of Utah School of Medicine, Salt Lake City, UT, USA Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. article info Article history: Received 4 February 2011 Received in revised form 8 August 2011 Accepted 17 October 2011 Keywords: Placebo analgesia Expectation Pain relief Dose-response Awareness Consciousness abstract Investigating dose-dependent effects of placebo analgesia (PA) in laboratory subjects undergoing pain testing, we evaluated 2 hypotheses: (1) greater expectancy for relief produces greater PA, and (2) cued expectancy for relief triggered by a predictive cue leads to more enhanced analgesia than does passive expectancy (no predictive cue). We used conditioning procedures in which 84 subjects experienced reduced stimulation intensity following the application of purported analgesic creams to the 2 experi- mental fingers, while the control finger received the same levels of stimulation as in the baseline block. The dose of placebos was manipulated by creating 2 levels of expectations for relief. The form of expec- tation (cued vs uncued) was also manipulated by a predictive cue specifying the next finger to be stim- ulated. Subjective reports and psychophysiological responses served as critical indicators for evaluating impacts of the placebo manipulation on subsequent pain processing. The dose-dependent PA was unam- biguously demonstrated by the predicted ordering of the 3 fingers (ie, manipulated expectation levels) in terms of both response sensitivity and average response magnitude, in mixed-effects analysis of 3 out- come indicators (evoked potential, skin conductance response, pain report). Greater expectation for relief led to both (1) greater reductions in the average dependent variable slope (response sensitivity) as a func- tion of stimulus intensity, and (2) greater reductions in average response magnitude. Unexpectedly, uncued expectation led to a slightly larger PA than did cued expectation. The study provided clear evi- dence that PA can occur in a ‘‘dose’’-dependent manner, mediated by the levels of expectancy for pain relief. Crown Copyright Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. All rights reserved. 1. Introduction Placebo research has entered into the final stage in the history of an artifact, the exploitation stage, in which the reality of place- bos is honored, and many scientifically genuine questions are cur- rently debated [25]. What has been most robust and consistently demonstrated is placebo analgesia (PA), a particular subclass of placebo response [20,42]. If a patient or a subject experiences a strong need for pain relief and expects to obtain relief from a treat- ment or a pill, part or all of this relief may come from psychological factors. Researchers have hypothesized a variety of direct mechanisms to account for PA. These include classical conditioning [61,62], changes in response expectancy [22,23], reduction in anxiety [18,47], and the release of endogenous opioids [30]. The current emerging consensus is that multiple factors working in concert contribute to the generation of PA [2,12,41,44]. In thinking about how psychological factors mediate PA, Price provided a cogent summary of 5 major theories of PA’s underlying mechanisms [42], and suggested that different general mecha- nisms proposed in the literature (eg, direct change in affective state, response expectancy, and activation of descending control mechanisms) share the idea that expectancy is a proximate psycho- logical mediator of PA [1,3,16,19,51]. Prior research documented that the dose of expectation affects the magnitude of the placebo response, both in the experimental setting [26] and in the clinical setting [40]. These studies investigated differential effects of instructions for drug delivery and documented that certain expec- tations are associated with a larger response magnitude than uncertain expectations. 0304-3959/$36.00 Crown Copyright Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. All rights reserved. doi:10.1016/j.pain.2011.10.024 ⇑ Corresponding author. Address: Department of Anesthesiology, Pain Research Center, Utah Center for Exploring Mind-Body Interactions (UCEMBI), University of Utah School of Medicine, 615 Arapeen Drive, Suite 200, Salt Lake City, UT 84108, USA. Tel.: +1 801 585 0419. E-mail address: yoshi.nakamura@utah.edu (Y. Nakamura). PAIN Ò 153 (2012) 227–237 www.elsevier.com/locate/pain