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The Placebo and Nocebo Phenomena: Their Clinical Management and Impact on Treatment Outcomes

  • Author Footnotes
    * These authors contributed equally to this work.
    Victor Chavarria
    Footnotes
    * These authors contributed equally to this work.
    Affiliations
    Institut de Neuropsiquiatria i Adiccions (INAD), Parc de salut Mar (PSM), Barcelona, Spain
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  • Author Footnotes
    * These authors contributed equally to this work.
    João Vian
    Footnotes
    * These authors contributed equally to this work.
    Affiliations
    Psychiatry and Mental Health Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal

    Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
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  • Círia Pereira
    Affiliations
    Psychiatry and Mental Health Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal

    Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
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  • João Data-Franco
    Affiliations
    Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    Departamento de Psiquiatria e Saúde Mental, Hospital Beatriz Ângelo, Lisboa, Portugal
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  • Brisa S. Fernandes
    Affiliations
    IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia

    Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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  • Michael Berk
    Affiliations
    IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia

    University Hospital Geelong, Barwon Health, Geelong, VIC Australia

    Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia

    Centre for Youth Mental Health, Parkville, VIC, Australia

    Florey Institute, University of Melbourne, Parkville, VIC, Australia
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  • Seetal Dodd
    Correspondence
    Address correspondence to: Seetal Dodd, MSc, PhD, University Hospital Geelong, Barwon Health, PO Box 281, Geelong, Victoria 3220, Australia.
    Affiliations
    IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia

    University Hospital Geelong, Barwon Health, Geelong, VIC Australia

    Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia

    Centre for Youth Mental Health, Parkville, VIC, Australia
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  • Author Footnotes
    * These authors contributed equally to this work.

      Abstract

      Purpose

      This overview focuses on placebo and nocebo effects in clinical trials and routine care. Our goal was to propose strategies to improve outcomes in clinical practice, maximizing placebo effects and reducing nocebo effects, as well as managing these phenomena in clinical trials.

      Methods

      A narrative literature search of PubMed was conducted (January 1980–September 2016). Systematic reviews, randomized controlled trials, observational studies, and case series that had an emphasis on placebo or nocebo effects in clinical practice were included in the qualitative synthesis. 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.

      Findings

      Placebo and nocebo effects are psychobiological events imputable to the therapeutic context. Placebo is defined as an inert substance that provokes perceived benefits, whereas the term nocebo is used when an inert substance causes perceived harm. Their major mechanisms are expectancy and classical conditioning. Placebo is used in several fields of medicine, as a diagnostic tool or to reduce drug dosage. Placebo/nocebo effects are difficult to disentangle from the natural course of illness or the actual effects of a new drug in a clinical trial. There are known strategies to enhance clinical results by manipulating expectations and conditioning.

      Implications

      Placebo and nocebo effects occur frequently and are clinically significant but are underrecognized in clinical practice. Physicians should be able to recognize these phenomena and master tactics on how to manage these effects to enhance the quality of clinical practice.

      Key words

      Introduction

      The placebo effect has been studied extensively throughout history.
      • Kerr C.E.
      • Milne I.
      • Kaptchuk T.J.
      William Cullen and a missing mind-body link in the early history of placebos.
      • Kaptchuk T.J.
      • Kerr C.E.
      • Zanger A.
      Placebo controls, exorcisms, and the devil.
      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.
      • Crichton F.
      • Petrie K.J.
      Accentuate the positive: counteracting psychogenic responses to media health messages in the age of the Internet.
      • Webster R.K.
      • Weinman J.
      • Rubin G.J.
      A systematic review of factors that contribute to nocebo effects.
      • Szemerszky R.
      • Dömötör Z.
      • Berkes T.
      • Köteles F.
      Attribution-based nocebo effects. perceived effects of a placebo pill and a sham magnetic field on cognitive performance and somatic symptoms.
      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 context
      • Finniss D.G.
      • Kaptchuk T.J.
      • Miller F.
      • Benedetti F.
      Placebo effects: biologival, clinical and ethical advances.
      ; 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 analgesia
      • Fields H.L.
      Neurophysiology of pain and pain modulation.
      • Voudouris N.J.
      • Peck C.L.
      • Coleman G.
      The role of conditioning and verbal expectancy in the placebo response.
      • Benedetti F.
      • Rainero I.
      • Pollo A.
      New insights into placebo analgesia.
      • Kong J.
      • Spaeth R.
      • Cook A.
      • et al.
      Are all placebo effects equal? Placebo pills, sham acupuncture, cue conditioning and their association.
      and irritable bowel syndrome (IBS).
      • Hall K.T.
      • Lembo A.J.
      • Kirsch I.
      • et al.
      Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome.
      These phenomena have been studied more recently in the field of dermatology
      • Bartels D.J.
      • Van Laarhoven A.I.
      • Haverkamp E.A.
      • et al.
      Role of conditioning and verbal suggestion in placebo and nocebo effects on itch.
      • Bartels D.J.
      • Van Laarhoven A.I.
      • Van De Kerkhof P.C.
      • Evers A.W.
      Placebo and nocebo effects on itch: effects, mechanisms, and predictors.
      • Napadow V.
      • Li A.
      • Loggia M.L.
      • et al.
      The imagined itch: brain circuitry supporting nocebo-induced itch in atopic dermatitis patients.
      and in psychiatry, particularly in depression.
      • Kirsch I.
      Antidepressants and the placebo effect.
      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.
      • Price D.D.
      • Finniss D.G.
      • Benedetti F.
      A comprehensive review of the placebo effect: recent advances and current thought.
      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.
      • Webster R.K.
      • Weinman J.
      • Rubin G.J.
      A systematic review of factors that contribute to nocebo effects.
      • Price D.D.
      • Milling L.S.
      • Kirsch I.
      • et al.
      An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm.
      • Amanzio M.
      • Benedetti F.
      Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems.
      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.
      • Reicherts P.
      • Gerdes A.B.
      • Pauli P.
      • Wieser M.J.
      Psychological placebo and nocebo effects on pain rely on expectation and previous experience.
      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.
      • Petrie K.J.
      • Broadbent E.A.
      • Kley N.
      • et al.
      Worries about modernity predict symptom complaints after environmental pesticide spraying.
      Misattribution may have a more significant role in nocebo effects than in placebo effects, although this theory remains a focus of active debate.
      • Colloca L.
      • Miller F.G.
      The nocebo effect and its relevance for clinical practice.
      • Enck P.
      • Bingel U.
      • Schedlowski M.
      • Rief W.
      The placebo response in medicine: minimize, maximize or personalize?.
      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.
      • Finniss D.G.
      • Kaptchuk T.J.
      • Miller F.
      • Benedetti F.
      Placebo effects: biologival, clinical and ethical advances.
      • Finniss D.G.
      • Benedetti F.
      Mechanisms of the placebo response and their impact on clinical trials and clinical practice.
      • Colloca L.
      • Benedetti F.
      Placebos and painkillers: is mind as real as matter?.
      A companion paper published in this issue of Clinical Therapeutics reviews the theoretical and biological underpinnings of the nocebo and placebo phenomena.
      • Dodd S.
      • Dean O.
      • Vian J.
      • Berk M.
      A review of the theoretical and biological understanding of nocebo and placebo phenomena.
      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.
      • Benedetti F.
      • Amanzio M.
      • Vighetti S.
      • Asteggiano G.
      The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect.
      In intellectually disabled patients, a higher intelligence quotient was positively related with placebo response.
      • Curie A.
      • Yang K.
      • Kirsch I.
      • et al.
      Placebo responses in genetically determined intellectual disability: a meta-analysis.
      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.
      • Lachman H.M.
      • Papolos D.F.
      • Saito T.
      • et al.
      Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders.
      It was suggested as a biomarker of placebo response in IBS and a potential biomarker of placebo response in other conditions.
      • Hall K.T.
      • Lembo A.J.
      • Kirsch I.
      • et al.
      Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome.
      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.
      • Furmark T.
      • Appel L.
      • Henningsson S.
      • et al.
      A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety.
      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.

      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 that had an emphasis on placebo or nocebo effects in clinical practice were selected for the qualitative synthesis.

      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.
      • Sherman R.
      • Hickner J.
      Academic physicians use placebos in clinical practice and believe in the mind-body connection.
      An English study found that only 12% of general practitioners use pure placebos (totally inert interventions) but the number was 97% for impure ones (interventions with clear efficacy for certain conditions but are prescribed for conditions in which their efficacy is unknown).
      • Howick J.
      • Bishop F.L.
      • Heneghan C.
      • et al.
      Placebo use in the United Kingdom: results from a national survey of primary care practitioners.
      The most common reason to use a placebo was to tranquilize the patient (18%) and as a supplemental treatment (18%). Other reasons included “after ‘unjustified’ demand for medication” (15%), “for nonspecific complaints” (13%), “after all clinically indicated treatment possibilities were exhausted” (11%), “to control pain” (6%), “to get the patient to stop complaining” (6%), and “as a diagnostic tool” (4%).
      • Sherman R.
      • Hickner J.
      Academic physicians use placebos in clinical practice and believe in the mind-body connection.
      It has been argued that the clinical benefits from many poorly evidence based complementary and alternative disciplines derive largely or even solely from cultivation of the factors that drive placebo effects.
      • Vickers A.J.
      Clinical trials of homeopathy and placebo: analysis of a scientific debate.
      Local regulations, however, preclude clinical use of placebos in some jurisdictions.
      Patients need a greater dose of analgesic to achieve an equivalent outcome if their placebo response is impaired. When patients with postoperative pain were given intravenous saline (placebo), and buprenorphine was made available on request, the group told that the intravenous saline was a powerful painkiller took 33% less analgesia for the same pain compared with a control group (who were told they were receiving a rehydrating solution).
      • Pollo A.
      • Amanzio M.
      • Arslanian A.
      • et al.
      Response expectancies in placebo analgesia and their clinical relevance.

      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.
      • Atlas L.Y.
      • Whittington R.A.
      • Lindquist M.A.
      • et al.
      Dissociable influences of opiates and expectations on pain.
      This outcome is concordant with the finding that drugs without therapeutic rituals are less effective.
      • Levine J.D.
      • Gordon N.C.
      Influence of the method of drug administration on analgesic response.
      A suitable therapeutic setting can thus enhance the placebo response.
      • Testa M.
      • Rossettini G.
      Enhance placebo, avoid nocebo: how contextual factors affect physiotherapy outcomes.
      The placebo effect has been well established in RCTs. In depression, its magnitude has been shown to vary depending on the investigators. Some propose that up to 75% of the drug effect is mediated by the placebo effect.
      • Kirsch I.
      • Sapirstein G.
      Listening to Prozac but hearing placebo: a meta-analysis of antidepressant medication.
      • Khan A.
      • Warner H.A.
      • Brown W.A.
      Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database.
      Others question these results, arguing that an unrepresentative subset of clinical trials (including many cases of mild to moderate depression) were analyzed, and therefore the data are not accurate.
      • Beutler L.E.
      Prozac and placebo: there’s a pony in there somewhere.
      • Klein D.F.
      Listening to meta-analysis but hearing bias.
      This theory suggests that patients with less severe depression have a lower biological substrate and are more vulnerable to the placebo effect. In 2002,
      • Kirsch I.
      • Moore T.J.
      • Scoboria A.
      • Nicholls S.
      The emperor’s new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration.
      a meta-analysis was conducted with US Food and Drug Administration data containing RCTs that had not been published. This study revealed a small significant difference between antidepressant drug and placebo but not a clinical difference; the mean difference between drug and placebo was ~2 points on the Hamilton Depression Rating Scale. An alternative hypothesis to explain this difference in antidepressant trials is breached blind. Because of the side effects of the drugs, the RCT patients may know if they are in the placebo or the active group.
      • Rabkin J.G.
      • Markowitz J.S.
      • Stewart J.
      • et al.
      How blind is blind? Assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and phenelzine.
      Furthermore, when another active antidepressant is used as the comparator, instead of placebo, there is a significant increase in the effectiveness of the drug.
      • Rutherford B.R.
      • Sneed J.R.
      • Roose S.P.
      Does study design influence outcome?.
      It remains controversial whether the placebo effect is increasing across time in RCTs of depression. It has been proposed that the placebo effect has progressively increased over time
      • Walsh B.T.
      • Seidman S.N.
      • Sysko R.
      • Gould M.
      Placebo response in studies of major depression: variable, substantial, and growing.
      within the general population as a result of inflation of baseline severity to meet threshold inclusion criteria; that is, trials with less ill people, in which regression to the mean is more likely, and more comprehensive and frequent assessment procedures. Others have argued that pharmaceutical companies try to select only severely depressed patients because pharmacotherapy RCTs for mild and moderate depression often do not show statistically significant separation between the treatment and placebo trial arms,
      • Kirsch I.
      • Deacon B.J.
      • Huedo-Medina T.B.
      • et al.
      Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration.
      thus downplaying the role of decreased baseline depression severity as an explanation. In contrast, a recent meta-analysis using published and unpublished data found stable placebo responses in the last 25 years,
      • Furukawa T.A.
      • Cipriani A.
      • Atkinson L.Z.
      • et al.
      Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies.
      implying the increase across time effect may be an artifact.

      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 disorders to chronic or mental disorders (which wax and wane, where the natural history of illness extends greatly in time or has poor or no biomarkers available).
      • Jewell N.P.
      Natural history of diseases: statistical designs and issues.
      Prospective nonintervention studies are increasingly ethically challenging as fewer diseases are lacking effective treatment. Therefore, in many cases, it is impossible to include a nontreatment arm in a clinical trial to guide our interpretation of results and discount the influence of natural progression. A loophole to this problem was found in studies of psychotherapy efficacy on major depressive disorder that use a wait-list as a control group. A meta-analysis
      • Rutherford B.R.
      • Sneed J.R.
      • Roose S.P.
      Does differential drop-out explain the influence of study design on antidepressant response? A meta-analysis.
      found that “wait-listers” experience ~33% of the symptomatic improvement of treated patients and 40% of the ones receiving placebo. An important caveat is that a wait-list is thus a very poor control group for clinical trials, despite being used often. Some studies even found that wait-list results in nocebo effects.
      • Furukawa T.A.
      • Noma H.
      • Caldwell D.M.
      • et al.
      Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta-analysis.

      Strategies (Using Placebo to Improve Results)

      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.
      • Enck P.
      • Bingel U.
      • Schedlowski M.
      • Rief W.
      The placebo response in medicine: minimize, maximize or personalize?.
      Positively influencing patients’ beliefs about therapeutic success is one way to maximize the placebo effect.
      • Barefoot J.C.
      • Brummett B.H.
      • Williams R.B.
      • et al.
      Recovery expectations and long-term prognosis of patients with coronary heart disease.
      However, being too optimistic is also ethically problematic and can be construed as disingenuous if one is not cautious. Manipulating a patient’s expectations may not necessarily require lying or deceiving. In a study of IBS, patients were informed they were being treated with placebo and still developed a positive clinical response.
      • Kaptchuk T.J.
      • Friedlander E.
      • Kelley J.M.
      • et al.
      Placebos without deception: a randomized controlled trial in irritable bowel syndrome.
      A partial reinforcement paradigm, placebo-controlled drug reduction (PCDR) (use of a full dose of medication for a set period of time [acquisition period] followed by a maintenance or evocation period with interposed placebo) has been shown to lower the dose needed to elicit a therapeutic response. This finding opens the door for a panoply of chronic disorders treated with medications with substantial side effects (Table I). PCDR allowed children with attention-deficit/hyperactivity disorder to be effectively treated with 50% of their optimal stimulant dose
      • Sandler A.D.
      • Glesne C.E.
      • Bodfish J.W.
      Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder?.
      and reduced the corticosteroid dose needed in psoriasis.
      • Ader R.
      • Mercurio M.G.
      • Walton J.
      • et al.
      Conditioned pharmacotherapeutic effects: a preliminary study.
      Table IStrategies to maximize the placebo effect.
      Managing ExpectationsConditioning
      Screen for patients with negative beliefsPlacebo-controlled drug reduction (PCDR)
      Hidden applications when discontinuing a drug expected to cause withdrawal symptomsUse salient stimuli and constant context when administering treatment including sensorial cues, same room and time of day when giving treatment
      Promote social contact with other successful patientsUse effective pretreatments
      Reduce anxietyAvoid extinction in long-term treatments
      Motivation strategies, changes in situational cues
      Enhance physician–patient relationship
      Empathic style, more time of contact
      Describe the procedure before executing to improve attention
      Adapted from Enck et al.
      • Enck P.
      • Bingel U.
      • Schedlowski M.
      • Rief W.
      The placebo response in medicine: minimize, maximize or personalize?.
      It is usually assumed that more complex, time-consuming, and invasive interventions are more likely to be associated with placebo effects than other interventions. For instance, different colors and sizes of a pill seem to influence the clinical outcome.
      • Huskisson E.C.
      Simple analgesics for arthritis.
      However, to our knowledge, only 1 systematic review
      • Fässler M.
      • Meissner K.
      • Kleijnen J.
      • et al.
      A systematic review found no consistent difference in effect between more and less intensive placebo interventions.
      has found mixed evidence of more invasive placebos having larger effects (7 of 12 studies with >1 placebo found no difference, 4 found single-outcome differences, and 1 found a large effect; 2 of 4 studies designed to differentiate placebo intensity were positive). The extant data may not be sufficient to discount its influence. To design studies directly comparing very different placebo interventions (ie, pill vs injection) while ensuring blinding for both patients and researchers ranges from very difficult to impossible. Also, to try to design studies controlling for context or for patient or clinician bias in expectancies might be a Sisyphean-like task, as the differences in context and expectancies themselves may be the cause of the placebo effect.
      Although the placebo could be more powerful, deliberately administering a more invasive or intense placebo may be both ethically challenging (especially one with potential to cause harm) and lacking in evidence. Conversely, a meta-analysis of 41 RCTs assessing the effects of antidepressant agents on major depressive disorder showed that the more follow-up observations that occur, the more intense are the placebo effects elicited.
      • Posternak M.A.
      • Zimmerman M.
      Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials: meta-analysis.
      The number of medical visits in clinical trials contrasts with the shorter contact in community settings. This strategy is well established and can be useful because it is nonharmful. Profiling or choosing the right person to try a placebo might be more problematic. There was limited evidence for the role of age or sex, at least in psychiatric disorders.
      • Weimer K.
      • Colloca L.
      • Enck P.
      Placebo effects in psychiatry: mediators and moderators.
      A stronger correlation was found for low symptom severity and short duration of illness. There were 2 studies in children reporting a higher placebo effect in those of non-white ethnic origin.
      • Newcorn J.H.
      • Sutton V.K.
      • Zhang S.
      • et al.
      Characteristics of placebo responders in pediatric clinical trials of attention-deficit/hyperactivity disorder.
      • Cohen D.
      • Consoli A.
      • Bodeau N.
      • et al.
      Predictors of placebo response in randomized controlled trials of psychotropic drugs for children and adolescents with internalizing disorders.

      Managing Placebo in Clinical Trials

      When comparing a drug versus a placebo, the first thing to bear in mind is that the effect of an active drug includes in itself a placebo component. Furthermore, issues are further complicated because the relation of the effects between the placebo and drug groups may not always be additive; that is, the measured effect in the active drug arm may be more (or less) than expected just by adding the placebo effect to the actual active drug effect.
      • Enck P.
      • Bingel U.
      • Schedlowski M.
      • Rief W.
      The placebo response in medicine: minimize, maximize or personalize?.
      • Muthen B.
      • Brown H.C.
      Estimating drug effects in the presence of placebo response: causal inference using growth mixture modeling.
      Therefore, perhaps “optimizing the drug–placebo difference” (vs minimizing placebo) is a preferable denomination.
      Designing clinical trials is a specialized field in its own right. Separating a drug effect from a placebo effect always at the core of a clinical trial design, so that general quality guidelines for a clinical trial usually will work to optimize the drug–placebo difference: standardizing for symptom severity; avoiding physician’s selection bias; controlling for center effects and patient adherence; and ensuring effective blinding.
      However, sometimes these strategies are accompanied by other undesirable effects. For example, if we identify drug responders during a run-in phase or preselect patients who were previously exposed to a similar drug, we may increase the drug–placebo difference, but we also risk limiting a drug indication and overestimating benefits. If the population of previous responders comprised a specific group (eg, women), the trial will never generate approval for men. Some strategies involve deceit and thus have ethical concerns. Cost and feasibility are concerns as well (eg, when considering augmenting sample size). Therefore, it is up to the researcher to weigh the risks and benefits of each strategy.
      Because the chance of being in a treatment group increases the magnitude of placebo responses,
      • Papakostas G.I.
      • Fava M.
      Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD.
      a study design of equal likelihood of receiving placebo or treatment (ie, avoid enrichment or multidosing studies) should be preferred. Contrary to common belief, trying to exclude placebo responders using run-in phases early in the study was not able to prevent later placebo response.
      • Quigley E.M.M.
      • Tack J.
      • Chey W.D.
      • et al.
      Randomised clinical trials: linaclotide phase 3 studies in IBS-C—a prespecified further analysis based on European Medicines Agency-specified endpoints.
      Randomized run-in (ie, in a double-blind manner, patients first start receiving placebo and are then switched to the active drug after a few days) and withdrawal periods seem to hold more promise.
      • Mallinckrodt C.
      • Chuang-Stein C.
      • McSorley P.
      • et al.
      A case study comparing a randomized withdrawal trial and a double-blind long-term trial for assessing the long-term efficacy of an antidepressant.
      Crossover designs may promote conditioning
      • Suchman A.L.
      • Ader R.
      Classic conditioning and placebo effects in crossover studies.
      and may lead to unblinding of the study due to perceived side effects. Using active placebos (drugs that mimic the active treatment side effects) is a possible perfect placebo that rarely exists, mimicking all the side effects without any of the active mechanisms of the drug being tested. Controlling for the natural progression of the disease should also be a concern, even if in many situations it is ethically challenging and may motivate subjects to drop out. A way around this is using Zelen’s design,
      • Zelen M.
      A new design for randomized clinical trials.
      in which patients are randomly divided into an observational group and an interventional group comprising the active drug and placebo branches, allowing to control for the natural course of illness.
      Comparative effectiveness trials are usually used when an efficacious treatment already exists for ethical standards. The new drug must then prove superiority, equivalence, or noninferiority. However, it has been shown that a drug tested against an active comparator performs better.
      • Papakostas G.I.
      • Fava M.
      Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD.
      • Woods S.W.
      • Gueorguieva R.V.
      • Baker C.B.
      • Makuch R.W.
      Control group bias in randomized atypical antipsychotic medication trials for schizophrenia.
      The placebo effect is also reportedly stronger when patients report the outcome than when the physician performs the assessment,
      • Rief W.
      • Nestoriuc Y.
      • Weiss S.
      • et al.
      Meta-analysis of the placebo response in antidepressant trials.
      which is itself stronger than a biomarker-based evaluation.
      • Hróbjartsson A.
      • Gøtzsche P.C.
      Placebo interventions for all clinical conditions.
      The most objective outcome possible is death or survival rate, but this approach obviously cannot be used for many disorder endpoints (Table II).
      Table IIStrategies to optimize drug–placebo differences in clinical trials.
      Avoid enrichment/multidosing studies
      Aim for a 50/50 probability of receiving placebo
      Use treatment-naive patients
      Randomized run-in and withdrawal periods
      Use active placebos
      Incorporate “no-treatment” groups
      Avoid comparative effectiveness trials
      Prioritize outcome evaluation in the following order:
       1. Death
       2. Biomarkers
       3. Physician assessment
       4. Patient-reported outcomes

      Minimizing Nocebo

      In the case of nocebo, no overt ethical dilemma is present. The intention of the physician is always to minimize its risk and effects. Also, we can expect the factors and strategies used to minimize the nocebo effect to be a mirror of the ones in placebo.
      Of major importance would be to identify individuals more prone to develop nocebo effects. Several studies have been conducted to identify “risk factors” of the nocebo effect. A systematic review
      • Webster R.K.
      • Weinman J.
      • Rubin G.J.
      A systematic review of factors that contribute to nocebo effects.
      found “learning/social observation,” “perceived dose,” “verbal suggestions of arousal and symptoms,” and “baseline symptom expectations” to be the strongest predictors of nocebo effects. Interestingly, the type of administration again did not appear to be relevant, nor did self-awareness during exposure. Symptom severity at baseline (one of the strongest associations with placebo) also produced mixed results. Demographic factors such as sex, age, and literacy did not change the risk of a nocebo response. One study found that female investigator subjects report nocebo effects twice as frequently as male subjects after a social suggestion paradigm, but these data could have been confounded by the study design (the social cue was presented by a female ).
      • Faasse K.
      • Grey A.
      • Jordan R.
      • et al.
      Seeing is believing: impact of social modeling on placebo and nocebo responding.
      In modern health systems in which access is good, participants who volunteer for trials may have presented with poor response or have not tolerated standard therapy. This earlier adverse experience increases the likelihood of these subjects being primed for nocebo responses.
      • Rheker J.
      • Winkler A.
      • Doering B.K.
      • Rief W.
      Learning to experience side effects after antidepressant intake—results from a randomized, controlled, double-blind study.
      Managing patients’ beliefs and experiences are at the core of possible strategies. Framing of information is an effective way to put the benefits and risks of treatment in perspective, focusing on the positive possibilities.
      • Edwards A.
      • Elwyn G.
      • Covey J.
      • et al.
      Presenting risk information—a review of the effects of “framing” and other manipulations on patient outcomes.
      A caring and empathic relationship is beneficial.
      • Di Blasi Z.
      • Harkness E.
      • Ernst E.
      • et al.
      Influence of context effects on health outcomes: a systematic review.
      When the medical problem allows for a small delay in the start of therapy, a lower initial dose might be helpful. Similarly, in RCTs, if a patient does not know when exactly he or she is getting exposed, nocebo effects are reduced (Table III). Nevertheless, this approach may be rarely feasible in outpatient settings or even time- and resource-consuming in a hospital setting.
      Table IIIStrategies to minimize nocebo.
      Managing ExpectationsConditioning
      Avoid informed consent overly focused on side effectsLow-dose initial regimen (when possible)
      Framing of informationHidden tapering in when feasible
      Focus on the positive effects of treatment
      Conjoint plan
      Sense of control and ownership of the decision-making process (by the patient)
      Empathic attitude
      Adapted from Data-Franco and Berk.
      • Data-Franco J.
      • Berk M.
      The nocebo effect: a clinicians guide.

      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, maximizing placebo and reducing nocebo in clinical practice, and enhancing results in clinical trials. It underlines the impact of creating a good physician–patient relationship, increasing empathic attitudes, exposing information suitably, decreasing expectations of adverse effects, and promoting social contact between successfully treated patients.

      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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