Chapter 6
Placebo/nocebo: a two‐sided coin in the clinician’s hand

Elisa Frisaldi¹, Aziz Shaibani², & Fabrizio Benedetti^1,3

¹ University of Turin Medical School, Neuroscience Department, Turin, Italy

² Nerve and Muscle Center of Texas, Baylor College of Medicine, Houston, Texas, USA

³ Medicine and Physiology of Hypoxia, Plateau Rosà, Switzerland

Introduction

The use of placebos dates back to the origins of medicine itself. Much of the ongoing confusion about the term, still pervading both the society and the scientific community, probably derives from the shifting focus on its different aspects across the centuries, such as: an inert medication given more to please than to benefit, a deceiving expedient to trick the naive layman, a means to detect the mystifying patient, a tool to isolate specific drugs effects in the course of clinical trials and, finally, an additional therapeutic aid. Current neurobiological and pharmacological evidence has placed placebo effects at the intersection between expectation, hope, desire, anxiety and previous experience (conditioning), involving both patient and attending staff, and has provided scientific ground for their exploitation. Interest in the placebo’s evil twin, the nocebo, is more recent. If a placebo is a sham treatment inducing a positive outcome, a nocebo is a sham treatment inducing a negative one. It could actually be the same inert substance (e.g. coupled to opposite verbal instructions to reverse the patient’s expectations). As for placebos, the whole context surrounding the therapeutic act impacts on different psychological aspects to produce the end result. In modern clinical practice, ethical concerns have been raised about the legitimacy of placebo administration. Informed consent and patient deceit seem irreconcilable; still a more widespread awareness of the importance of the patient–provider interaction and the introduction of specific therapeutic protocols can represent a way to exploit placebo effects to the patient’s advantage while at the same time avoiding nocebo effects.

In this chapter a brief overview on current knowledge of the biology of placebo and nocebo effects is outlined, followed by some suggestions for clinical application. Emphasis is on pain studies and pain treatment, but it should be remembered that placebo and nocebo effects have been described in many other clinical conditions, such as Parkinson’s disease and depression; in different systems, like the endocrine and immune systems; and even outside the medical domain, as in sport performance. Indeed, they pervade our everyday life, at the conscious and unconscious level, affecting our evaluations and decisions.

The interested reader is referred to a number of reviews and books that address these topics in greater detail [1–7].

Before we begin: a few facts on placebo/nocebo

Q1: Is the placebo effect the same as the placebo response?

A. The two terms are often used synonymously. However, a recent consensus paper stated that the placebo response is that observed in the placebo arm of a clinical trial, which is produced by the placebo biological phenomenon in addition to other potential factors contributing to symptom amelioration, such as natural history, regression to the mean, biases and judgment errors. The placebo effect, on the other hand, designates the biological phenomenon in isolation, as can best be studied in specifically designed experimental protocols [8].
Q2: Is the placebo an inert treatment?

A. Yes and no. The adjective “inert” correctly suggests that the substance or treatment is devoid of specific effects for the condition being treated. However, it cannot by definition be inert if it produces an effect. The solution to the conundrum can be found by shifting the attention from the treatment to the patient who receives it: it is in fact the symbolic meaning of the treatment, rather than the treatment itself, which by different mechanisms triggers active processes in the patient’s brain, ultimately producing the placebo effect. The placebo need not be a “treatment” either. Its archetype is, of course, the sugar pill, but more subtle or more general factors work equally well. For example, the symbolic meaning can be ascribed to one or all aspects of the context surrounding the therapeutic act, and the simulation of a therapeutic situation can thus adequately replace the sugar pill.
Q3: Is a nocebo effect the opposite of a placebo effect?

A. Yes, the nocebo has been defined as negative placebo. As expectations of amelioration can lead to clinical improvement, expectations of worsening can result in negative outcome. The term nocebo (Latin “I shall harm”) was originally introduced to designate noxious effects produced by a placebo (e.g. side effects of the drug the placebo is substituting for). In that case, however, the negative outcome is produced in spite of an expectation of benefit. True nocebo effects, on the other hand, are always the result of negative expectations, specific or generic (like a pessimistic attitude).

Proposed mechanisms of placebo/nocebo effects

Different explanatory mechanisms have been proposed for both placebo and nocebo effects, each supported by experimental evidence. They need not be mutually exclusive and can actually be at work simultaneously.

Classical conditioning

This theory posits the placebo/nocebo effect as the result of Pavlovian conditioning. In this process, the repeated co‐occurrence of an unconditioned response to an unconditioned stimulus (e.g. salivation after the sight of food) with a conditioned stimulus (e.g. a bell ringing) induces a conditioned response (i.e. salivation that is induced by bell ringing alone). Likewise, aspects of the clinical setting (e.g. taste, color, shape of a tablet, as well as white coats or the peculiar hospital smell) can also act as conditioned stimuli, eliciting a therapeutic response in the absence of an active principle, just because they have been paired with it in the past. In the same way, the conditioned response can be a negative outcome, as in the case of nausea elicited by the sight of the environment where chemotherapy has been administered in the past. Classical conditioning seems to work best where unconscious processes are at play, as in placebo/nocebo effects involving endocrine or immune systems, but it has also been documented in clinical and experimental placebo analgesia and nocebo hyperalgesia.

Expectations

This theory conceives the placebo effect as the product of cognitive engagement, with the patient consciously foreseeing a positive or negative outcome, based on factors as diverse as verbal instructions, environmental clues, previous experience, emotional arousal and the interaction with care‐providers. This anticipation of the future outcome in turn triggers internal changes resulting in specific experiences (e.g. analgesia or hyperalgesia). Desire, self‐efficacy and self‐reinforcing feedback all interact with expectation, potentiating its effects. Desire is the experiential dimension of wanting something to happen or wanting to avoid something happening [7], while self‐efficacy is the belief to be able to manage the disease, performing the right actions to induce positive changes (e.g. to withstand and lessen pain). Self‐reinforcing feedback is a positive loop whereby the subject attends selectively to signs of improvement, taking them as evidence that the placebo treatment has worked. This is also called the somatic focus (i.e. the degree to which individuals focus on their symptoms) [7]. A related proposed mechanism posits that anxiety reduction also has a role in placebo responses, because the subject interpretation of ambiguous sensations is changed from noxious and menacing to benign and unworthy of attention.