Placebo effects in health and disease : how expectations shape treatment outcomes

The context in which a medical treatment is administrated influences treatment outcomes. As of today, the health care system has little knowledge about the non-specific components that contribute to the positive effect of a given therapy, often referred to as the placebo component, and how this may be harnessed in order to maximize treatment effects. The overreaching aim of this doctoral thesis is to investigate the impact of non-specific treatment components on clinical outcomes, in particular the role of expectations. More specifically, this thesis focuses on two clinically relevant, yet poorly investigated, topics: 1) Are placebo effects dependent on higher order cognitions? This was investigated among patients with intellectual disability (ID) and in an experimental setting in healthy individuals. 2) Are placebo effects affected by the duration of a chronic disease? In order to study this, outcomes from a randomized controlled trial (RCT) among fibromyalgia (FM) patients were analyzed. Study I investigated the influence of non-conscious expectations on placebo analgesia, using an implicit priming task called Scrambled Sentence Test (SST). Healthy participants were randomized to receive positive or neutral expectations via the SST, followed by a placebo manipulation with a sham analgesic device. Results demonstrated no effect of implicit priming on placebo analgesia, yet the study indicates that placebo analgesia is largely explained by prior experience of pain relief, and that the social interaction with a trustworthy clinician may have competed with the possible effect of implicit priming. Study II examined the relationship between placebo analgesia and the time (months, years) a person has been exposed to chronic disease, by assessing placebo responses in a pharmacological trial in patients with FM. Results revealed that FM duration was associated with baseline pain levels as well as placebo analgesia. These results point to the importance of early FM interventions, as the chance to harness endogenous pain regulation and to avoid chronification may be higher early in the disease course. Study III investigated how treatment expectations may shape outcomes in pharmacological clinical trials among patients with ID. The placebo component in ID clinical trials was examined by performing a meta-analysis comparing drug responses in open-label trials (with 100% certainty of getting the real drug) with drug responses in placebo-controlled trials (with 50% chance of getting the real drug). The results demonstrated placebo effects among patients with ID, as the effect of the real drug in open-label context was associated with better treatment outcomes than the same drug in a placebo-controlled context. Our study validates the notion that patients with ID are influenced by contextual factors in clinical trials in spite of severe cognitive deficits. LIST OF SCIENTIFIC PAPERS I. Rosén A, Yi J, Kirsch I, Kaptchuk T, Ingvar M, Jensen K. Effects of subtle cognitive manipulations on placebo analgesia – an implicit priming study. Accepted in The European Journal of Pain (2016) II. Kosek E, Rosén A, Carville S, Choy E, Gracely RH, Vitton O, Marcus H, Petzke F, Ingvar M, Jensen K. The effect of pain chronification on placebo analgesia: Lower placebo responses after long-term exposure to fibromyalgia pain. In revision III. Jensen K, Kirsch I, Pontén M, Rosén A, Yang K, Gollub R, Portes V, Kaptchuk T, Curie A. Certainty of genuine treatment increases drug responses among intellectually disabled patients. Under review