Placebo and nocebo effects are known to contribute significantly to the response to symptom control, including analgesia. Clinical trial methodologies using placebo controls are designed to identify the magnitude of these effects in the research context. An adequately powered, randomized, double-blind, placebo-controlled trial of ketamine in cancer pain has recently been reported, which demonstrated no net clinical benefit for ketamine over and above that of placebo. Rates of placebo and nocebo responses were high. The setting of a clinical trial provides an opportunity to quantify the nonpharmacologic aspects of patient responses to analgesia, raising important clinical and ethical issues for practice. The findings of the ketamine study are analyzed in the context of a methodological discussion of placebo and nocebo effects, what is known about the biological and psychological bases for each of these, and their implications for a clinical trial design in the palliative care setting. Along with reviewing the use of ketamine after this negative trial, clinicians need to remain aware of the strength and significance of both placebo and nocebo responses in their own practices and the biopsychosocial complexity of why and how patients actually respond to pain management strategies. The results of this study strongly reinforce the importance of the therapeutic relationship and the context of care. �� 2013 Published by Elsevier Inc. on behalf of U.S. Cancer Pain Relief Committee. All rights reserved.