Approaches to a Complex Phenomenon

There is probably no other human phenomenon that better reflects the inseparable interaction between psychological and somatic factors than the placebo effect. This phenomenon is a complex psychobiological process consisting of learning and expectancy components acting on neurophysiological systems, and its efficacy has been confirmed empirically in a range of fields such as pain and the immune system. Inert substances such as sugar pills can trigger placebo effects, and these effects can also enhance the response to active treatments.

This topical issue presents the complexity of the phenomenon called placebo effect. The articles included here describe different research approaches to the topic and look at different models and facets of the placebo phenomenon.

During the past decades the most impressive demonstrations of these effects have been presented in the field of pain and placebo analgesia. The effectiveness of analgesic placebo responses remains unchallenged and our knowledge about the underlying mechanisms that produce the placebo effect is expanding rapidly. Together with expectancy theories, classical conditioning has been discussed as being a major explanatory model. However, other learning principles, such as social learning (via vicarious reinforcement), are thought to play an important role in the development and maintenance of placebo analgesia. From a neurobiological viewpoint, research findings have revealed the involvement of cortical, subcortical, and recently spinal structures in the placebo-induced modulation of pain that cognitively triggers the release of endogenous opioid and non-opioid substances (Colloca, Klinger, Flor, & Bingel, 2013).

Insights into the underlying mechanisms and the neurobiological foundation (Colloca et al., 2013) of the analgesic placebo effect have now made it possible to develop principles for clinical application (Klinger, Colloca, Bingel, & Flor, 2014). These principles must, of course, be justifiable within ethical boundaries. In their article addressing this issue, Colloca, Jonas, Killen, Miller, and Shurtleff (2014) point out that, in the current state of medicine, there are numerous examples of inappropriate uses of placebos, often justified by the patient’s urgency for help on the one hand, and the lack of appropriate medication on the other. The authors emphasize the need to focus on elements of the clinical encounter and the patient-physician relationship to increase the placebo effect. Clearly caution is necessary in harnessing placebo effects in medicine to treat patients while avoiding deception. Accordingly, the study of the placebo effect should be incorporated in the core clinical practice curriculum of all health practitioners.

Benedetti, Amanzio, and Maggi (1995) and Colloca, Lopiano, Lanotte, and Benedetti (2004) showed that pain treatments (e.g., opioids) consist of a verum component (active pharmacological component) and a placebo component. Regarding the latter, there are many contextual factors associated with the treatment, such as expectancy, fear, previous experiences with clinical staff, and co-interventions, but also illness-related factors and personality variables. It is necessary to boost these specific aspects systematically to ultimately enhance the analgesic effect. In Germany, for instance, this innovative thought has already been implemented in the S3 guidelines of the working group of scientific medical societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF – see www.awmf.org); this association represents Germany in the Council for International Organizations of Medical Sciences, CIOMS) for the “treatment of acute and perioperative pain.” It is recommended therein to use the potential of the placebo effect in the clinical context and to avoid nocebo effects (Klinger, Thomm, Bryant, & Becker, 2009). The placebo effect has thereby become more acceptable amongst health practitioners. It is important to note that the aim is explicitly not to replace effective pain medication with placebos but to recognize the placebo effect as an additive component that can optimize every pain medication beyond its pure pharmacology-based effectiveness. This paradigm shift toward the explicit use of the placebo effect offers a completely new opportunity for the prevention and treatment of chronic pain. Therefore, the clinical value of the placebo effect needs to be discussed with patients. This approach should involve using psychological strategies in assisting the patient to establish positive, yet realistic expectations regarding the medical pain treatment.

Placebo effects are highly specific. Finniss, Kaptchuk, Miller, and Benedetti (2010) described 12 different mechanisms of placebo effects. Keeping this in mind, one can think of the placebo effect as being a form of mimicry of bodily procedures caused by the medication. For example, analgesic placebos activate the endorphin system, and placebos used as Parkinson disease medication activate dopamine in the striatum and change the activity of neurons in the basal ganglia and the thalamus. However, a specific mechanism is not always detectable. The underlining placebo mechanisms of antidepressant drugs seem to be somewhat dubious. In his provocative paper on antidepressants and the placebo effect published in this issue, Kirsch (2014) shows that regardless of contradictory mechanisms of antidepressant medication, antidepressant placebos are almost as effective as antidepressants, yet eliciting far fewer side effects.

Vase, Skyt, Petersen, and Price (2014) review placebo and nocebo effects in chronic pain patients and reveal the influence of expectations and emotions on the experience of pain. In a further review, Sölle, Bartholomäus, Worm, and Klinger (2014) show how classical conditioning and expectancy produce placebo effects with itching. Vits and Schedlowski (2014) review the current literature about learned placebo effects in the immune system.

Carlino, Benedetti, and Pollo (2014) focus on placebo effects on physical performance and show how it can be can manipulated via verbal suggestions, whilst Geers, Rose, Fowler, and Brown (2014) look at patient involvement in treatment decision-making and show that, depending on patients’ prior experience with treatments, this involvement can enhance or hinder placebo effects, respectively. Hofmann, Wrobel, Kessner, and Bingel (2014) demonstrate that carry-over effects after treatment failure can be minimized by changing the route of application, for example, a pill replaced by a cream. Kamping, Müller, Klinger, Schmitz, and Flor (2014) also focus on chronic pain patients. They consider the influence of attitude, experience, and expectation on the placebo effect and present an instrument to assess both specific attitudes toward pain medication and experiences with pain medication.

The similarity between pain and itching sensations suggests a transfer of the placebo analgesic effect to anti-itching medication. Finally, the current state of placebo research holds sufficient evidence for careful considerations of clinical implications of placebo effects. Employing the placebo effect according to its mechanisms and strictly following the underlying mechanisms in the development and the maintenance of the placebo effect is required.