The first part of the theme issue summarizes and discusses placebo mechanisms across medical fields, focusing on different explanatory models including conditioning, verbal suggestions, emotions, motivation, spirituality and healing rituals. The second part of the issue focuses on questions related to transfer of that knowledge into clinical practice, discussing implications of placebo research for the design and interpretation of clinical trials, for the therapeutic settings in daily patient care and for future translational placebo research.
Benedetti's team provides a comprehensive overview of neurobiological and pharmacological mechanisms underlying the placebo effect across different conditions [28
]. While most of the presented studies are related to the medical context, where pathological conditions are altered following the administration of an inert substance or verbal instructions tailored to induce expectation of change, the review also goes beyond the clinical setting, embracing physical performance with crucial implications for sport competition as well.
Schedlowski's team presents behavioural conditioning as a major mechanism mediating the placebo response on the immune system, and describes underlying mechanisms on the basis of functional interaction between the central nervous system (CNS) and the peripheral immune system, with an emphasis on allergic reactions [24
]. Although the exact mechanisms of immune behavioural conditioning are yet largely unknown, there is evidence that both allergic and anti-allergic responses can be ‘manipulated’ by means of conditioning paradigms, with the potential to promote anti-allergic healing processes.
Specific verbal suggestions accompanying placebo interventions affect not only the perception of symptoms, but also the functioning of inner organs that are modulated by the ANS. Karin Meissner [22
] reviews the placebo literature with respect to the cardiovascular, the gastrointestinal and the pulmonary systems and provides relevant background information on the functional organization of the ANS and the central autonomic network. In accordance with previous findings from analgesic placebo research [59
], her results provide first evidence for the autonomic specificity of autonomic placebo effects. For example, placebo interventions targeting the stomach affected gastric motility, but not cardiovascular or electrodermal functions [61
]. She proposes that verbal suggestions during placebo interventions may activate association networks in the brain that store memories of the appropriate autonomic response [22
In contrast to findings supporting the specificity of placebo effects, it has been postulated that there might be a common mechanism that subserves all types of placebo responses. Flaten et al
] review the literature with respect to a hypothesis that focuses on the role of emotions for the placebo response. The hypothesis predicts that pain relief following the ingestion of a placebo pill may be due to the reduction of stress and anxiety and a concomitant increase in positive emotions. As these emotions are closely connected to the activation of endogenous opioid systems in the brain, they can explain the occurrence of analgesic placebo responses.
An important question related to the effectiveness of placebo interventions is whether insights into placebo and nocebo mechanisms gained under laboratory conditions can be transferred to the clinical encounter. Starting from a motivational framework of placebo effects, Michael Hyland [32
] provides evidence that different placebo mechanisms may apply in different contexts. Whereas response expectancy, conditioning and goal activation may be responsible for short-term placebo effects, long-term placebo responses may be achieved through satisfaction of higher level goals, such as a good relationship with the doctor. This may improve symptoms by reducing stress and thereby attenuating the deleterious effects of stress on health.
In the last years, a new research field has blossomed that is investigating the relationship between spirituality, health and coping with illness and distress. Spirituality may broadly be understood as an implicit or explicit orientation towards, searching for and expressing a reality transcending immediate and mediate personal needs, and a striving for experiencing a universal or transcendental dimension. It is of interest that research looking into spirituality health connection has provided insights that are similar to those obtained in placebo research. For example, there is clear evidence that spirituality is able to alter pain perception [62
]. Kohls et al
] suggested that meaningfulness and sense of purpose may be a concept relevant for health-related processes including the placebo effect.
Ted Kaptchuk's contribution [33
] is a creative comparative analysis of ceremonials by Navajo healing rituals (the most populous American Indian tribe in the United States), acupuncture, and biomedical treatments. The author describes the different components of the three healing settings and identifies the treatment ritual as the basis of any placebo response. While for biomedicine the placebo effect has primarily been a ‘non-specific’ process that needs to be controlled, the placebo effect for ritual theory constitutes the ‘specific’ effect of a healing effort. As placebo research has started to sketch the underlying neurobiological causal pathways of these unspecific effects, it has become clear that a link between placebo studies and ritual theory would be helpful. The author emphasizes the need for mixed-method research methodologies in the field.
The last contribution of the first part provided by Colloca & Miller [27
] aims at interpreting, critiquing and conceptualizing the existing experimental and clinical research on placebo (and nocebo) effects though a learning perspective—the process of decoding information and creating expectations. The question whether and how human beings can activate this sort of inbuilt ‘endogenous pharmacy’ is of utmost interest for all areas of medicine. It is important to understand how individuals can systematically harness innate, environmentally and/or culturally promoted placebo mechanisms for enhancing clinical outcomes, improving their health and well-being, and reducing harmful effects. Therefore, the learning perspective may have innovative implications for a deeper and better knowledge of the placebo phenomenon in science and healthcare.
The second part of the issue covers highlights that range from clinical trial methodology to translational placebo research. Harald Walach [44
] introduces the reader to historical notes of the placebo effect when inert substances and procedures were introduced as control conditions. He then describes the efficacy paradox of sham interventions pointing to the fact that sham interventions frequently turn out to be more powerful than proved, evidence-based treatments. Walach uses the efficacy paradox as a conceptual basis for discussing the limits of present conventional trial methodology, thereby raising questions about how efficacy of treatments should be determined. The question whether a treatment is effective can be addressed by considering circumstances, context, patients' choice, and subjective sense of meaningfulness that is attributed to the intervention itself.
Rief's team provides an overview about placebo and nocebo phenomena in antidepressant trials [43
]. The authors present a sophisticated meta-analysis of RCTs suggesting large placebo responses to antidepressant medication. Several moderating factors relating to the size of the placebo responses could be identified, such as the method of symptom assessment and year of publication. Nocebo responses, in terms of the side-effect patterns in the placebo groups, depended on the side-effect profiles of the antidepressant drug and notably differed for gender.
Enck et al
] focus on important but as yet unanswered questions about placebo effects in clinical trials, with an emphasis that questions the additivity model. They propose several novel study designs that may be useful for disentangling placebo and treatment effects in clinical trials in order to get a more reliable and true estimation of the effects of active treatments. For example, a unique although still untested study design would not randomize patients between drug and placebo, but would allow them to ‘freely’ choose between two pills, one being the active drug and one the placebo. Thus, the assessment of drug versus placebo efficacy would not rely on reports of symptom improvement that may contain reporting bias, but rather on choice behaviour.
Linde et al
] discuss reasons for using placebos in clinical practice and suggest that the perspectives of physicians, scientists and patients about placebo may substantially diverge. Using placebo interventions in medical practice is rather frequent, but is in contrast with the professional imperative of specific and indicated treatment as it is conventionally taught in medical education, and consequently points to a considerable amount of treatment uncertainty among physicians. At the same time, the widespread use of placebos can be taken as evidence that rituals, myths and plausible explanations have not been barred from modern medicine but still guide therapeutic decisions.
Wayne Jonas [58
] discusses some possible dilemmas that may derive from the current framing of placebo research. In particular, he presents the scenario of a physician who has to decide on the utilization of a treatment that is ‘not better than placebo’ but nonetheless is more effective than standard care. In such a case, Jonas argues, it is important to understand the placebo effect as a meaning response, which can be triggered by manipulating contextual factors. By introducing the concept of an optimal healing environment, Jonas suggests that the therapeutic alliance and the management of patient's expectation may represent an important element of good clinical practice.
Verbal and non-verbal interactions between the patient and the physician may affect the perception of treatment efficacy, which in turn may influence patient expectations, and thus also clinical outcome. Vase et al
] present qualitative data from interviews with patients who have experienced pain relief following a placebo intervention or active treatment, discussing the extent to which these findings have implications for our understanding of placebo analgesia.
Beyond the scientific interest in exploring the mechanisms of the placebo and nocebo responses and improving clinical trial methodology, the ultimate aim of this research is to develop knowledge that can be translated into improved patient care. In light of the translational placebo research, Colloca & Miller [30
] end the issue by analysing salient aspects of theoretical knowledge of the placebo and nocebo effects, discussing the evidence of clinical placebo (and nocebo) responses, and identifying potential strategies for harnessing beneficial placebo responses and diminishing harmful nocebo effects in the clinical encounter consistent with ethical and legal requirements.