ReviewThe Placebo and Nocebo Phenomena: Their Clinical Management and Impact on Treatment Outcomes
Introduction
The placebo effect has been studied extensively throughout history.1, 2 The nocebo effect, also called “the evil brother of the placebo effect,” has been less studied, but in recent years has become a subject of growing interest.3, 4, 5 Both phenomena are composed of several intertwined biological and environmental mechanisms, displaying a complex interaction. Their operative mechanisms not only are affected by the characteristics of the individuals but also on the context in which they operate; thus, the search for a simple equation to predict the effect of placebo and nocebo has been met with limited success.
A precise definition of the placebo and nocebo phenomena is difficult to pinpoint, as different researchers have used different definitions, often depending on the context. A starting definition would be psychobiological events attributable to the overall therapeutic context6; herein, placebo effect would be the benefits provoked by an inert substance, and the nocebo effect is the induction of true or perceived harm after treatment with an inactive substance. Thus, a response to treatment, not attributable to the known mechanism of action of the treatment, is the core feature of both phenomena. This means that the definition can also be applied to an active substance treatment, then referring to the (extra) effects it elicits and that are not explained by its pharmacologic action. Many disorders have a natural course of illness in which symptoms fluctuate, making it difficult to differentiate between a placebo or nocebo response and the natural course of illness at an individual patient level. Similarly, many “side effects” occur commonly with or without pharmacotherapies (eg, headache), making it often difficult to disentangle, at an individual patient level, between a treatment-emergent adverse event that is a nocebo response or one that has occurred independently of treatment.
Paradigmatically, the placebo and nocebo phenomena have been most extensively studied in analgesia7, 8, 9, 10 and irritable bowel syndrome (IBS).11 These phenomena have been studied more recently in the field of dermatology12, 13, 14 and in psychiatry, particularly in depression.15
The underpinnings of placebo and nocebo are psychological and neurobiological. Psychological mechanisms include expectancies, conditioning, learning, memory, motivation, somatic focus, reward, anxiety reduction and meaning, and “placebo-by-proxy” induced by clinicians and family members.16 Two principal mechanisms are well supported. The first aspect involves expectancy: the administration of placebo creates expectations in future responses by using simple verbal cues as modulators of expectations. Researchers can nudge a subject׳s expectations and boost the placebo effect. The second aspect involves classical conditioning: repeated associations between a neutral stimulus and an unconditioned stimulus (active drug) can result in the ability of the neutral stimulus by itself to provoke a response characteristic of the unconditioned stimulus.4, 17, 18 In a study of placebo/nocebo in thermal pain, neither conditioning nor expectation alone seemed to be able to elicit placebo or nocebo effects; however, the combination of experience (conditioning) and expectation resulted in significant placebo (analgesia) or nocebo (hyperalgesia) effects.19
Misattribution is the inappropriate attribution of improvement or worsening to a treatment when it was actually caused by the disorder’s natural fluctuation of symptoms or other causes.20 Misattribution may have a more significant role in nocebo effects than in placebo effects, although this theory remains a focus of active debate.21, 22
The neurobiology of the response to placebo and nocebo has been studied mostly in the paradigmatic field of analgesia and has been shown to be mainly related to the opioid and dopaminergic pathways.6, 23, 24 A companion paper published in this issue of Clinical Therapeutics reviews the theoretical and biological underpinnings of the nocebo and placebo phenomena.25
It is important to note that placebo and nocebo responses are highly variable across individuals. Some individual differences have been associated with genetic polymorphisms or underlying neurologic impairments. For example, patients with frontal lobe impairment, especially prefrontal lobe, have decreased expectancy and learning, and thus they partially or totally lose their placebo response. In a study of Alzheimer׳s disease and pain, patients with reduced Frontal Assessment Battery scores exhibited a reduced placebo component of the analgesic treatment.26 In intellectually disabled patients, a higher intelligence quotient was positively related with placebo response.27
Catechol-O-methyl transferase is involved in dopamine degradation, affecting the prefrontal lobe. The catechol-O-methyl transferase Val158Met polymorphism is a G to A mutation leading to amino acid substitution at codon 158 in the transmembrane form of the enzyme.28 It was suggested as a biomarker of placebo response in IBS and a potential biomarker of placebo response in other conditions.11 Thus, people who carry this polymorphism are more likely to experience the placebo effect.
The tryptophan hydroxylase-2 polymorphism (serotonin-related gene) seems a significant predictor of clinical placebo response in social anxiety disorder. Homozygosity for the G allele was associated with serotonergic modulation of amygdala activity and greater improvement in symptoms of anxiety.29 People who experience anxiety disorder and carry this polymorphism are more likely to experience the placebo effect. Thus, psychological and neurobiological factors can predict individual differences in placebo and nocebo response.
The present review first focuses on the impact of placebo and nocebo effects in routine clinical settings as well as in clinical trials, and then offers strategies on how to use that knowledge to improve the quality of care and results in research.
Section snippets
Materials and Methods
A literature search of PubMed was conducted for articles published between January 1980 and September 2016. Search terms included: placebo, nocebo, clinical, clinical trial, clinical setting, placebo effect, nocebo effect, adverse effects, and treatment outcomes. This search was augmented by a manual search of the references of the key articles and the related literature. Systematic reviews, randomized controlled trials (RCTs), observational studies, and case series were identified. Articles
Clinical Application
The clinical understanding of the placebo effect is a relevant issue. Placebo responses may be a major driver of clinical change after diverse therapies. Placebos are used in several fields of medicine (eg, neurology, psychiatry, rheumatology, pain management, ophthalmology), although ethical considerations limit their use in some areas. When surveyed, 45% of American physicians admitted to having used a placebo.30 An English study found that only 12% of general practitioners use pure placebos
Challenges in Clinical Trials
The placebo or nocebo response is related to common biochemical pathways that are activated both by social stimuli and therapeutic rituals on one hand and by drugs on the other. It has been shown that when an opioid agent is administered, it binds to μ-opioid receptors, but the very same μ-opioid receptors are activated by the patient’s expectations about the drug.34 This outcome is concordant with the finding that drugs without therapeutic rituals are less effective.35 A suitable therapeutic
Placebo/Nocebo and Separation from the Natural Course of Illness
Understanding the natural course of illness is essential before commencing a clinical trial design or trying to separate drug from placebo effects. Given the fact that symptom severity does not stay frozen in time when no intervention is applied, the spontaneous progress or improvement of a pathological process can obviously confound or pose as a placebo or nocebo effect. These types of studies present numerous challenges, especially as modern medicine shifts its attention from infectious
Maximizing Placebo
Patient expectations contribute toward the outcome of several disorders. This has been demonstrated for analgesia, treatment of myocardial infarction and Parkinson’s disease, deep brain stimulation, orthopedic surgery, and antidepressant treatment.22 Positively influencing patients’ beliefs about therapeutic success is one way to maximize the placebo effect.50 However, being too optimistic is also ethically problematic and can be construed as disingenuous if one is not cautious. Manipulating a
Conclusions
Clinically, placebo and nocebo effects are of major importance, being present in daily medical practice. The overall effect of a drug stems from its pharmacodynamic actions plus the psychological effect derived from the act of its administration. Although both placebo and nocebo have been widely studied, the full complexity of their mechanisms needs further definition. Thus, when correctly applied, there are a number of strategies that can improve responses and patients’ quality of life,
Conflicts of Interest
The authors list no conflicts of interest in connection with this work. There was no funding support for this work.
Acknowledgments
Dr. Berk is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (GNT1059660). All contributors to this manuscript are listed as co-authors. Michael Berk is supported by a NHMRC Senior Principal Research Fellowship (1059660). All authors were involved in all aspects of preparing this review paper, including the literature search and writing.
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These authors contributed equally to this work.