Are Blue Pills Better Than Green? How Treatment Features Modulate Placebo Effects

Abstract

Treatment-related expectations are important predictors for placebo effects in various medical conditions. They are formed by verbal and nonverbal cues during the administration of treatments, such as verbal suggestions, conscious and unconscious associations with previous treatments, characteristics of patients and health-care providers as well as perceptual characteristics of the treatment. This review provides an overview of studies that aimed to elucidate the impact of treatment characteristics on expectations and placebo effects. Results show that high price, brand label, the use of invasive placebos and high placebo dose increase the expectations toward the beneficial effect of a placebo treatment, which in turn boost the placebo effect. Neuroimaging studies provide first insights into the neurobiological mechanisms underlying these differential placebo effects.

Introduction

Treatment-related expectations have been shown to be an important predictor for placebo effects in various medical conditions (Meissner et al., 2011; Price, Finniss, & Benedetti, 2008; Schedlowski, Enck, Rief, & Bingel, 2015). For example, a pill administered with verbal information that it is a potent analgesic can significantly reduce pain, even when the pill is pharmacologically inert. Expectations regarding the effectiveness of treatments can be formed via different psychological mechanisms, including verbal suggestions and associative learning (Colloca & Miller, 2011). Research in the recent decades has clearly shown that expectation effects are deeply rooted in our brains. For example, placebo analgesia is accompanied by activation of a specific pain modulating network that extends from cortical areas to the spinal cord (Geuter, Koban, & Wager, 2017). In addition to pain, placebo effects have been demonstrated for nausea (Müller, Remus, Hoffmann, Tschöp, & Meissner, 2016; Quinn & Colagiuri, 2014), depression and anxiety (Meyer et al., 2015; Peciña et al., 2015; Rutherford et al., 2016), gastrointestinal and cardiovascular functions (Kaptchuk et al., 2008; Meissner, 2009; Meissner & Ziep, 2011; Rief et al., 2017), Parkinson's disease (De la Fuente-Fernández et al., 2001), and immune responses (Hadamitzky, Sondermann, Benson, & Schedlowski, 2018; Pacheco-López, Engler, Niemi, & Schedlowski, 2006). In this regard, it is important to emphasize that placebo effects can be elicited and exploited not only by the administration of placebo interventions, but also by maximizing the placebo component of any active intervention. This has been impressively demonstrated by studies in which patients received pharmacological drugs either overtly or covertly (i.e., via an intravenous line from a separate room): The improvements were larger and occurred earlier when the patients knew when to expect a beneficial effect of a treatment (Colloca, Lopiano, Lanotte, & Benedetti, 2004).

However, not only verbal information accompanying treatments, but also nonverbal cues can affect the size of expectancies toward a medical treatment, and thus the size of the placebo effect. For example, there is increasing evidence from experimental and clinical studies that more invasive and more expensive placebo interventions are systematically associated with larger placebo effects (Bannuru et al., 2015; Faasse, Martin, Grey, Gamble, & Petrie, 2016; Fehse, Maikowski, Simmank, Gutyrchik, & Meissner, 2015; Geuter, Eippert, Attar, & Büchel, 2013; Kaptchuk et al., 2006; Meissner et al., 2013). A thorough review of these studies is important to get an idea of what an optimized placebo intervention might look like.