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How to make sense of the placebo effect in clinical practice

Slawomir Wojniusz, Associated Professor at MUSK Health Research Group, OsloMet and Cognitive Health in Trauma and Disease research group, Oslo University Hospital

New insights into the mechanisms behind the placebo effect have led to a growing debate about how it can be exploited in clinical practice. As a consequence, a number of articles recommending ways of utilization of the placebo effect have appeared. This trend raises some important questions: Should we adjust our approaches to facilitate the occurrence of placebo effects? If so, how should we go about doing so? And would doing so even be considered ethical?

Instead of directly answering these questions, I will try to present an alternative look at placebo effects throughout the rest of this text – a view that makes them, in practical terms, uninteresting.

Historical perspective on placebo

The term placebo originates from the Latin verb “placeō”, which means, “I shall please”. In the Encyclopedia of Behavioral Medicine (2013) placebo is defined as:

Any inert substance, procedure, apparatus, or similar, that alone has no effect in the body” [1].

In other words, the placebo relates to all types of interventions that in themselves should have no impact on the course of a patient’s illness.

Before World War II the use of placebo modalities e.g. bread or sugar pills, colored water etc., was common and was not considered problematic or unethical. In 1903, Richard Cabot (1868–1939), a distinguished professor at Harvard Medical School, described the placebo’s influence as follows:

He was brought up, as I suppose every physician is, to use placebo, bread pills, water subcutaneously, and other devices… How frequently such methods are used varies a great deal I suppose with individual practitioners, but I doubt if there is a physician in this room who has not used them and used them pretty often…I used to give them by the bushels” [2].

In that era, the placebo treatment was considered safe, although in medical terms ineffective. It was first and foremost applied to please and comfort the patient in order to“ smooth [the patient’s] path”, especially the “ignorant…disappointed and displeased.. hopeless, [and] incurable case[s]” [3].

The role of placebo started to change in the 1950s. One of the most influential papers on this subject, “The powerful placebo”, was published in 1955 by Henry Beecher, who proposed a new, important role for placebo:

the use of this tool is essential…to distinguish pharmacological effects from the effects of suggestion and….to obtain an unbiased assessment of the result of experiment” [4].

This new view of placebo coincided with massive advances in medicine, just when many incurable diseases were successfully tackled with potent antibiotics and vaccination programs.  A need for systematic evaluation of the efficacy of new drugs was apparent. As a result, the randomized placebo controlled trial became the gold standard for testing the effects of drugs and other treatment modalities. Furthermore, the development of more patient centered and less paternalistic approaches to treatment led to further changes with regards to ethical standards; deceiving the patient through the application of biologically ineffective placebo treatments was no longer considered acceptable. Hence, during the last decades of the 20th century the term ‘placebo’ was reserved either to describe randomized controlled trials or as a derogatory term for postulated effects of alternative or dubious treatment approaches. Many researchers have even denied its existence, explaining the observed effects as part of the natural course of disease, or as regression to the mean and methodological biases, such as unregistered extra treatments received outside the study, or flawed randomization and blinding procedures [2]. The notion that placebo is a form of “cheating” has not disappeared in modern times. It is still present today despite all the new insights into its working mechanisms. Nevertheless, the first decade of the 2nd millennium has brought with it a gradual change when it comes to  how we view placebo effects, as a result of discoveries concerning their neurobiological effects. Today, there is no doubt, that placebo effects elicit specific, psychoneurobiological responses. Here, I will only provide a brief summary of the neurobiological mechanisms behind the placebo effect. For a more detailed description of the involved mechanisms, please see a brilliant article by Testa and Rossettini called “Enhance placebo, avoid nocebo: How contextual factors affect physiotherapy outcomes” [5].

A modern era in placebo – neurobiological mechanisms

The majority of the placebo/nocebo research has been concerned with explaining their effects on pain. Recent findings indicate that placebo and nocebo phenomena are closely connected to the activity of the so called Descending Pain Modulatory System (DPMS), the same system that plays a central role in modulation of nociceptive and persistent pain. DPMS acts through a number of neuronal pathways employing different neurotransmitters and neurohormones including endogenous opioids, cannabinoids, dopamine, oxytocin and vasopressin [6, 7]. The DPMS brain regions that are shown to be active in placebo responses include; dorsolateral prefrontal cortex, rostral anterior cingulate cortex, amygdala and periaqueductal gray [8]. The involved brain areas, neurotransmitters and neurohormones are essential in processes related to pain, emotion regulation, reward seeking and social interactions. Furthermore, neuroimaging studies indicate that reduced pain ratings during placebo interventions also coincides with decreased activity in brain areas associated with classical pain processing, and that the pain-related activity in the ipsilateral dorsal horn, corresponding to painful stimulation is reduced under placebo [8]. Placebo effects may also be partially or fully blocked by naloxone, an opioid receptor antagonist, which is  proof of the neurobiological nature of the placebo effect [9].

Although pain has been the main focus of placebo research, the effects are not only limited to pain. For example, in Parkinson patients, increased dopamine production in the striatum was observed in conjunction with placebo treatment, and found to improve the patients’ motor function [10]. Placebo treatment has also been found to influence the immune system and related diseases [11]. Similarly, placebos have also been shown to modulate function of other inner-organs systems, e.g. pulmonary, gastrointestinal and cardiovascular [8].

Overall, the evidence shows that the placebo effect should be understood in a system dynamics perspective, where functioning of many biological and physiological systems in the body is dynamically and simultaneously influenced. Hence, placebo responses represent a complex interplay of biological, physiological, cognitive, emotional, social and environmental factors that need to be accounted for when it comes to explanation and exploitation of placebo responses.

Magic behind a phenomenon that “does not work”

According to its definition, a placebo is a substance, procedure or similar that alone has no effect in the body. Paradoxically, however, this is, a self-contradictory definition since the placebo effect would be an effect of something that “…has no effect in the body”. In practice, it means that the observed effect must be mediated by other processes triggered by the application of a placebo. The single most important message here is that these processes are not specifically dependent on the usage of placebo remedies, but also take place when valid, scientifically proved treatments are applied. In other words, the so-called placebo effects take place independently of whether we use sugar pills or meta-analysis validated, muscle strengthening protocols. Therefore, talking about placebo effects in clinical practice makes little sense. For clinicians, insights from placebo research are important to understand the relationship between, the body, psyche and environment, which will enable us to manipulate contextual factors for the benefit of overall treatment outcomes.

Psychological mechanisms behind the placebo effect/placebo effects

Although neurobiological findings explain the basic mechanisms behind the placebo effect, the psychological aspects of this phenomenon are perhaps even more interesting, as they can be influenced in a therapeutic setting. Most literature identifies two specific psychological mechanisms behind the placebo effect: the first one involves positive expectations towards treatment outcome; the second one is related to learning mechanisms involved in classical conditioning [12].

Positive expectations towards treatment can be induced by verbal instructions and explanations, which is generally known and accepted by health care professionals. However, different contextual factors may additionally influence expectations in an unconscious way, for example, through social observation, e.g. analgesic responses have been shown to occur after subjects have observed other persons undergoing analgesic treatment [13]. Other contextual factors shown to influence placebo responses may include the appearance of health care professionals, medical facilities, treatment tools, smell, color, shape and size of tools and medications, interactions with other people, etc. [14]. Another interesting aspect of this is trying to understand through which psychological mechanisms influencing expectations seem to work. Although research in this area is limited,  four different pathways have been suggested [15]:

  1. Anxiety reduction pathway promoted by clinical communication that contributes to reduction of activity in threat-related centers in the brain.
  2. Positive affectivity pathway, where anticipating a beneficial treatment outcome increases positive feelings stimulating dopaminergic reward mechanisms in the brain.
  3. Interpretative pathway, where expectations modify attention, detection and interpretation of somatic experiences in a non-conscious way.
  4. The associative pathway, where different cues may activate simple previously established associative responses.

Simply put, positive expectations towards treatment may reduce anxiety around the condition, increase positive emotions, e.g. encourage more optimistic views of the future, give hope, strengthen motivation, change cognitions about the condition, reduce attention towards symptoms and so on. In modern medical practice all those “pathways” are in fact already considered important in treating any type of condition and particularly multifactorial and persistent ones. In this respect “the placebo effect/s” is already integrated with modern standards for high quality clinical encounters between patients and health care professionals. The knowledge we gain from the placebo research field can, on the other hand, make us even more aware of how therapy outcomes might be influenced and thus enable us to further optimize the context to achieve maximum gains. It is thus important that the effects of specific procedures, e.g. strengthening exercises, soft tissue treatment, etc., are not viewed independently but in the context of these effects. Although, the quantification of individual contributions of all involved factors is a difficult task, their effects should be seen in a system dynamics perspective; changes in one system may reinforce/multiply the actions of other systems and the other way around. The interdependencies are not limited to the physiological systems alone but have implications for the behavior of the patients that will in turn further influence physiological systems, e.g. reduced anxiety about the condition and positive emotions might influence health related behaviours such as level of physical activity or eating habits.

“Mindset matters” example

The Mindset matters study [16] might be considered as an example of far reaching interdependencies between various physiological systems and behaviour. Eighty-four female room attendants working in seven different hotels were measured on physiological health variables affected by exercise. Those in the informed condition were told that the work they do (cleaning hotel rooms) is good exercise and satisfies the Surgeon General’s recommendations for an active lifestyle. Subjects in the control group were not given this information. After 4 weeks, the informed group showed a decrease in weight, blood pressure, body fat, waist-to-hip ratio, and body mass index. They perceived themselves to be more active than at the baseline but did not in fact report any changes in their actual physical activity levels, e.g. training outside of work.  The authors suggest that the observed physiological changes might be a placebo effect, but it is unclear how these effects were mediated. The design of the study unfortunately does not allow us to draw any meaningful conclusions. However, having a positive mindset and positive emotions might have influenced their stress hormones levels, eating behavior and/or daily activity (e.g. taking the stairs instead of the elevator) and may in this way have impacted body weight and physiological parameters. The study is also a good example of the difficulties one might come across with regards to estimation of the contributions of various contextual factors for overall clinical outcome.

Influencing the context in practical terms

Since many different contextual factors influence the outcome, the question that remains is: how should we employ the knowledge about them in practice? Although some general guidelines are well known, i.e. how to create a positive patient-therapist relationship etc., these only pertain to a small piece of the bigger puzzle. Furthermore, our patients differ a lot and specific recommendations will never be beneficial for all of them. It might therefore be useful to shift our perspective towards a more philosophical level, abstracting the placebo effect away from its neurobiological nature. In 1997, Howard Brody proposed a so-called ‘meaning model’ of the placebo effect/s. In its essence the model suggests that a placebo response  is most likely to occur when the meaning attached to the illness experience is altered in a positive direction [17]. In layman terms, the treatment should make as much sense as possible for the patient. For example, it is not always necessary for the patient to understand every detail of the treatment procedure, or what exactly is going on in the brain during pain modulation. However, the explanation provided and the practical approach should be as meaningful as possible for the patient, eliciting positive emotions and confidence that the treatment works. For some patients a detailed science-based explanation will be appropriate, but for others it might be more meaningful to use a non-scientific metaphor. Furthermore, meaning is also created through non-verbal cues. The model emphasizes the importance of symbols in communication. In that sense, treatment becomes a symbol based ritual. The procedures and artifacts that are associated with good treatment outcomes will thus mobilize self-healing in patients, reinforcing the effect of the treatment. Moreover, the most powerful symbols and rituals will differ between cultures and settings. Using contexts in a way that promotes confidence in the treatment and in the therapist, is therefore an art.  It is, however, a very different art form to that of giving the patient a sugar pill and saying that this is a fantastic new drug. In a clinical context, the usage of placebo remedies is therefore neither necessary nor desirable in order to achieve the desired outcome.

Conclusion

The so-called placebo effect always plays a role in any type of clinical encounter, independently of whether the applied modality is a pure placebo or evidence based. Furthermore, the specific treatment effect and the so-called placebo effect will always interact, and reinforce or diminish each other, and further influence the self-healing process. Separating specific, therapeutic factors from contextual factors effects just does not seem to make sense. We should rather integrate both of them into our approaches in a natural and elegant way promoting the positive meaning of the treatment, e.g. as my old psychiatry professor used to simply put it when addressing his patients: “Antidepressants work, you just need to wish them welcome.”

 

References

  1. Gellman, M.D. and J.R. Turner, Encyclopedia of behavioral medicine. Springer reference. 2013, New York: Springer. 4 volumes.
  2. Kaptchuk, T.J., Powerful placebo: the dark side of the randomised controlled trial. Lancet, 1998. 351(9117): p. 1722-5.
  3. Pepper, O.H.P., A note on placebo. Am J Pharm, 1945. 117: p. 409-412.
  4. Beecher, H.K., The powerful placebo. J Am Med Assoc, 1955. 159(17): p. 1602-6.
  5. Testa, M. and G. Rossettini, Enhance placebo, avoid nocebo: How contextual factors affect physiotherapy outcomes. Man Ther, 2016.
  6. Carlino, E. and F. Benedetti, Different contexts, different pains, different experiences. Neuroscience, 2016. 338(Supplement C): p. 19-26.
  7. Finniss, D.G. and F. Benedetti, Mechanisms of the placebo response and their impact on clinical trials and clinical practice. Pain, 2005. 114(1-2): p. 3-6.
  8. Meissner, K., et al., The Placebo Effect: Advances from Different Methodological Approaches. The Journal of Neuroscience, 2011. 31(45): p. 16117-16124.
  9. Amanzio, M. and F. Benedetti, Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci, 1999. 19(1): p. 484-94.
  10. Lidstone, S.C., Great expectations: the placebo effect in Parkinson’s disease. Handb Exp Pharmacol, 2014. 225: p. 139-47.
  11. Vits, S., et al., Behavioural conditioning as the mediator of placebo responses in the immune system. Philos Trans R Soc Lond B Biol Sci, 2011. 366(1572): p. 1799-807.
  12. Carlino, E., A. Pollo, and F. Benedetti, Placebo analgesia and beyond: a melting pot of concepts and ideas for neuroscience. Curr Opin Anaesthesiol, 2011. 24(5): p. 540-4.
  13. Colloca, L. and F. Benedetti, Placebo analgesia induced by social observational learning. Pain, 2009. 144(1-2): p. 28-34.
  14. Benedetti, F., Placebo and the new physiology of the doctor-patient relationship. Physiol Rev, 2013. 93(3): p. 1207-46.
  15. Geers, A.L. and F.G. Miller, Understanding and translating the knowledge about placebo effects: the contribution of psychology. Curr Opin Psychiatry, 2014. 27(5): p. 326-31.
  16. Crum, A.J. and E.J. Langer, Mind-set matters: exercise and the placebo effect. Psychol Sci, 2007. 18(2): p. 165-71.
  17. Miller, F.G. and L. Colloca, Semiotics and the placebo effect. Perspect Biol Med, 2010. 53(4): p. 509-16.

 

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