Deception in Research on the Placebo Effect

DOI: 10.1371/journal.pmed.0020262.g001 Deception in Research on the Placebo Effect 0 Franklin G. Miller and David Wendler are in the Department of Clinical Bioethics, National Institutes of Health , Bethesda , Maryland, United States of America. Leora C. Swartzman is in the Department of Psychology, University of Western Ontario , London, Ontario , Canada. The opinions expressed are those of the authors and do not necessarily reflect the position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services 1 , David Wendler , Leora C. Swartzman Tfascinating yet puzzling he placebo effect is a phenomenon, which has challenged investigators over the past 50 years. Recently, it has been defined as the positive physiological or psychological changes associated with the use of inert medications, sham procedures, or therapeutic symbols within a healthcare encounter [1]. Increasing scientific inquiry has been aimed at elucidating the mechanisms responsible for placebo effects and determining how inert interventions can lead to positive changes in patients [1,2]. The majority of placebo mechanism research has been done within the context of experimental and clinical pain. Patients' expectations for improvement, also referred to as response expectancies, are thought to be one of the central mechanisms responsible for placebo effects [3-5]. Brain imaging techniques are being used to explore both the neurophysiological correlates of these expectations and the mechanisms underlying placebo effects in a variety of contexts, including pain relief in healthy participants, relief of symptoms of depression, and motor functioning in patients with Parkinson disease [6-8]. Understanding these mechanisms is an important step in harnessing the placebo effect in patient care. In the words of a National Institutes of Health request for applications, understanding how to enhance the therapeutic benefits of placebo effect in clinical practice has the potential to significantly improve healthcare [9]. Toward that end, the National Institutes of Health invited submissions for systematic studies aimed at discerning the psychosocial factors (including expectancy) in the patient-clinician relationship and/or in the health-care environment that can potentiate healing. - Response expectancy is seen to be a major driving force behind the placebo effect. Therefore, a common (and some would argue, necessary) feature of research aimed at elucidating placebo mechanisms is the use of deception in experimental manipulation of participants expectations (e.g., about whether or not they will receive a powerful pain killer or a sugar pill), while holding constant the pharmacological (or other) properties of the administered intervention. This research has clearly shown (across a wide range of clinical conditions) that altering expectancies for improvement has an impact on therapeutic outcomes [8,1013]. The tension between scientific methods for elucidating the placebo effect and ethical norms for conducting research involving human participants is illustrated most clearly by the balanced placebo design, an approach designed to disentangle the relative effects of pharmacology and response expectancy. Table 1 displays the balanced placebo design in a way that highlights the deception of participants that occurs in two of the four arms of the design. Table 1. The Balanced Placebo Design What Participants Are Told DOI:10.1371/journal.pmed.0020262.t001 What Participants Receive Participants Given Drug Participants Given Placebo In the balanced placebo design, investigators manipulate both expectancies (e.g., informing participants that they will receive a drug versus informing them that they will receive placebo) and the pharmacological agent (giving a drug versus giving a placebo). As reviewed by Swartzman and Burkell, researchers using this paradigm with healthy volunteers have shown that expectation plays a role in the subjective and behavioral effects of a range of psychoactive substances [14]. These substances include dexamfetamine, alcohol, caffeine, nicotine, and tetrahydrocannabinol [1519]. The balanced placebo design offers a powerful and elegant approach to evaluate drug versus expectancy effects and their interactions. As Kirsch notes, this design yields information that cannot be obtained from conventional clinical trials [20]. It provides a direct assessment of the drug effect, independent of expectancy, and the nondeceptive arms are more ecologically valid than the doubleblind administration in conventional randomized trials (i.e., they mimic what goes on in the real world of clinical practice). Thus, it is not surprising that Caspi recently suggested that the balanced placebo design be used more often in clinical trials of drug efficacy [21]. Despite the methodological virtues of the balanced placebo design, and its prior use in healthy volunteers, we are unaware of any trials that have employed this approach with patients. Clinical investigators likely have avoided use of the balanced placebo design out of concern for the ethical acceptability of deceiving patients. An often cited article on the balanced placebo design characterized the deception in the following way: Although deception is involved, it is no greater than is involved in any study using placebos [22]. However, this defense of the balanced placebo design confuses the ethical issues it raises. Placebo-controlled trials aimed at evaluating the efficacy of treatments may be regarded as having an element of deception, since the placebo control is designed to appear indistinguishable from the active treatment under investigation. Nevertheless, when these studies are conducted under effective double-blind conditions, participants are told that they will receive either a drug or a placebo, and neither the investigators nor the research participants know which intervention is received by any of the participants. Accordingly, administering the When deception is used, a conflict between the means and ends of scientific investigation ensues. study interventions, unlike the situation of the balanced placebo design, does not involve intentionally false communication; it requires investigators to withhold information, but not to lie to participants about the interventions they will receive. Research designed to understand the placebo effect by deceptively manipulating the expectations of participants holds great promise for understanding the psychological and neurobiological dimensions of healing. However, to pursue this research while respecting participants, it is necessary to develop an approach that reconciles the outright deception involved in placebo research, including the balanced placebo design, with the ethical norms governing clinical research. What Makes Deception in Scientific Investigation Ethically Problematic? At the outset, it is useful to appreciate the confl (...truncated)