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The Placebo and Nocebo Phenomena: Their Clinical Management And Clinical Therapeutics/Volume 39, Number 3, 2017 Review The Placebo and Nocebo Phenomena: Their CrossMark Clinical Management and Impact on Treatment Outcomes Victor Chavarria, MD1,*; Joa˜o Vian, MD2,3,*;Cı´ria Pereira, MD2,3; Joa˜o Data-Franco, MD3,4; Brisa S. Fernandes, MD, PhD5,6; Michael Berk, MBBCh, MMed(Psych), FF(Psych)SA, PhD, FRANZCP, FAAHMS5,7,8,9,10; and Seetal Dodd, MSc, PhD5,7,8,9 1Institut de Neuropsiquiatria i Adiccions (INAD), Parc de salut Mar (PSM), Barcelona, Spain; 2Psychiatry and Mental Health Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; 3Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; 4Departamento de Psiquiatria e Sau´de Mental, Hospital Beatriz Aˆngelo, Lisboa, Portugal; 5IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia; 6Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil; 7University Hospital Geelong, Barwon Health, Geelong, VIC Australia; 8Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia; 9Centre for Youth Mental Health, Parkville, VIC, Australia; and 10Florey Institute, University of Melbourne, Parkville, VIC, Australia ABSTRACT Findings: Placebo and nocebo effects are psychobio- Purpose: This overview focuses on placebo and logical events imputable to the therapeutic context. nocebo effects in clinical trials and routine care. Our Placebo is defined as an inert substance that provokes goal was to propose strategies to improve outcomes in perceived benefits, whereas the term nocebo is used when clinical practice, maximizing placebo effects and re- an inert substance causes perceived harm. Their major ducing nocebo effects, as well as managing these mechanisms are expectancy and classical conditioning. phenomena in clinical trials. Placebo is used in several fields of medicine, as a Methods: A narrative literature search of PubMed diagnostic tool or to reduce drug dosage. Placebo/nocebo was conducted (January 1980–September 2016). System- effects are difficult to disentangle from the natural course atic reviews, randomized controlled trials, observational of illness or the actual effects of a new drug in a clinical studies, and case series that had an emphasis on placebo trial. There are known strategies to enhance clinical or nocebo effects in clinical practice were included in the results by manipulating expectations and conditioning. qualitative synthesis. Search terms included: placebo, Implications: Placebo and nocebo effects occur fre- nocebo, clinical, clinical trial, clinical setting, placebo quently and are clinically significant but are underrecog- effect, nocebo effect, adverse effects,andtreatment out- nized in clinical practice. Physicians should be able to comes. This search was augmented by a manual search of recognize these phenomena and master tactics on how to the references of the key articles and the related literature. manage these effects to enhance the quality of clinical *These authors contributed equally to this work. Scan the QR Code with your phone to obtain Accepted for publication January 30, 2017. FREE ACCESS to the articles featured in the http://dx.doi.org/10.1016/j.clinthera.2017.01.031 Clinical Therapeutics topical updates or text 0149-2918/$ - see front matter GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed. & 2017 Elsevier HS Journals, Inc. All rights reserved. March 2017 477 Clinical Therapeutics practice. (Clin Ther. 2017;39:477–486) & 2017 Elsevier include expectancies, conditioning, learning, mem- HS Journals, Inc. All rights reserved. ory, motivation, somatic focus, reward, anxiety reduction Key words: adverse effects, clinical trial, nocebo, and meaning, and “placebo-by-proxy” induced by clini- pharmacology, placebo, treatment. cians and family members.16 Two principal mecha- nisms are well supported. The first aspect involves expec- tancy: the administration of placebo creates expectations INTRODUCTION in future responses by using simple verbal cues as modu- The placebo effect has been studied extensively through- lators of expectations. Researchers can nudge a subject's out history.1,2 The nocebo effect, also called “the evil expectations and boost the placebo effect. The second brother of the placebo effect,” has been less studied, but aspect involves classical conditioning: repeated associa- in recent years has become a subject of growing tions between a neutral stimulus and an unconditioned – interest.3 5 Both phenomena are composed of several stimulus (active drug) can result in the ability of the neu- intertwined biological and environmental mechanisms, tral stimulus by itself to provoke a response characteristic displaying a complex interaction. Their operative mech- of the unconditioned stimulus.4,17,18 In a study of placebo/ anisms not only are affected by the characteristics of the nocebo in thermal pain, neither conditioning nor expect- individuals but also on the context in which they operate; ation alone seemed to be able to elicit placebo or nocebo thus, the search for a simple equation to predict the effect effects; however, the combination of experience (con- of placebo and nocebo has been met with limited success. ditioning) and expectation resulted in significant placebo A precise definition of the placebo and nocebo pheno- (analgesia) or nocebo (hyperalgesia) effects.19 mena is difficult to pinpoint, as different researchers have Misattribution is the inappropriate attribution of used different definitions, often depending on the context. improvement or worsening to a treatment when it was Astartingdefinition would be psychobiological events actually caused by the disorder’s natural fluctuation of attributable to the overall therapeutic context6; herein, symptoms or other causes.20 Misattribution may have placebo effect would be the benefits provoked by an inert a more significant role in nocebo effects than in substance, and the nocebo effect is the induction of true placebo effects, although this theory remains a focus or perceived harm after treatment with an inactive sub- of active debate.21,22 stance. Thus, a response to treatment, not attributable to The neurobiology of the response to placebo and the known mechanism of action of the treatment, is the nocebo has been studied mostly in the paradigmatic field core feature of both phenomena. This means that the of analgesia and has been shown to be mainly related definition can also be applied to an active substance to the opioid and dopaminergic pathways.6,23,24 treatment, then referring to the (extra) effects it elicits and A companion paper published in this issue of Clinical that are not explained by its pharmacologic action. Many Therapeutics reviews the theoretical and biological disorders have a natural course of illness in which underpinnings of the nocebo and placebo phenomena.25 symptoms fluctuate, making it difficult to differentiate It is important to note that placebo and nocebo between a placebo or nocebo response and the natural responses are highly variable across individuals. Some course of illness at an individual patient level. Similarly, individual differences have been associated with genetic many “side effects” occur commonly with or without polymorphisms or underlying neurologic impairments. pharmacotherapies (eg, headache), making it often For example, patients with frontal lobe impairment, difficult to disentangle, at an individual patient level, especially prefrontal lobe, have decreased expectancy between a treatment-emergent adverse event that is a and learning, and thus they partially or totally lose their nocebo response or one that has occurred independently placebo response. In a study of Alzheimer's disease and of treatment. pain, patients with reduced Frontal Assessment Battery Paradigmatically, the placebo and nocebo phenomena scores exhibited a reduced placebo component of the – have been most extensively studied in analgesia7 10 and analgesic treatment.26 In intellectually disabled patients, a irritable bowel syndrome (IBS).11 These phenomena have higher intelligence quotient was positively related with been studied more recently in the field of dermato- placebo response.27 – logy12 14 and in psychiatry, particularly in depression.15 Catechol-O-methyl transferase is involved in dopa- The underpinnings of placebo and nocebo are psycho- mine degradation, affecting the prefrontal lobe. The logical and neurobiological. Psychological mechanisms catechol-O-methyl transferase Val158Met polymorphism 478 Volume 39 Number 3 V. Chavarria et al. is a G to A mutation leading to amino acid substitution but the number was 97% for impure ones at codon 158 in the transmembrane form of the (interventions with clear efficacy for certain conditions enzyme.28 It was suggested as a biomarker of placebo but are prescribed for conditions in which their efficacy response in IBS and a potential biomarker of placebo is unknown).31 The most common reason to use a response in other conditions.11 Thus, people who carry placebo was to tranquilize the patient (18%) and as a this polymorphism are more likely to experience the supplemental treatment (18%). Other reasons included placebo effect. “after ‘unjustified’ demand for medication” (15%), The tryptophan hydroxylase-2 polymorphism (seroto- “for nonspecific complaints” (13%), “after all nin-related gene) seems a significant predictor of clinical clinically indicated treatment possibilities were
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