Placebo effect and therapeutic context: A challenge in clinical research

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Placebo means an inert treatment, without therapeutic properties. Placebo effect is the response produced by the administration of a placebo. Placebo effect and placebo response are equivalent. These definitions contain a great paradox: How is it possible that something inert generates a response? If something is inert, by definition, it is incapable of producing responses.The word placebo is a conjugation of the Latin verb placere, which means to please, to gratify, to satisfy. The placebo effect appeared with force in the scientific community after World War II, following Henry Beecher's article “The powerful placebo” published in the JAMA journal, in 1955. Beecher treated soldiers that had been wounded during the war. He observed that in some of them, the pain could be mitigated with a saline solution and that this produced effects similar to morphine. Thirty-five percent of patients responded positively to placebo treatment.<a class="elsevierStyleCrossRef" href="#bib0305">1</a>Beecher's work on placebo was the beginning of medicine's modern era, where the randomized clinical trial represents the gold standard for evaluating the efficacy of an intervention. However, Beecher overestimated the placebo effect because it did not differentiate it from other bias or confounding factors, such as, for example, the natural course of the disease or regression to the mean. Since then there has been a growing interest in researching the placebo effect, especially in the last 15 years.In a broad sense, the placebo effect refers to improvements in the symptoms of patients that are attributable to their participation in a therapeutic encounter, with its rituals, symbols and interactions.The patient–therapist relationship implies a therapeutic ritual composed of a multitude of signs and symbols that are consciously and unconsciously perceived. These perceived messages are interpreted by patients, generating expectancy and conditioning.<a class="elsevierStyleCrossRef" href="#bib0310">2</a> We emphasize verbal and non-verbal communication, empathy, touch, gaze, enthusiasm, predisposition to listen and respond, trust, diagnostic and therapeutic tools, technology use, office or hospital room appearance, appearance of the waiting room, the white dressing gown, the stethoscope and the type of intervention (a pill or a physical agent).<a class="elsevierStyleCrossRef" href="#bib0315">3</a> This context is always present when a patient is subject to an intervention, whether we administer a tablet containing sugar or a tablet containing a potent analgesic. The tablet may be inert but the context is not.<a class="elsevierStyleCrossRef" href="#bib0320">4</a>The placebo effect is based on complex neurobiological mechanisms involving neurotransmitters (e.g. endorphins, cannabinoids and dopamine) and the activation of specific and quantifiable areas of the brain: the prefrontal cortex, the anterior insular cortex, the rostral anterior cingulate cortex, and the amygdala, areas related to anticipation and reward.<a class="elsevierStyleCrossRefs" href="#bib0325">5,6</a> Many drugs also act through these pathways.Recently, genes that predispose to a higher placebo response are being identified.Current evidence shows that the therapeutic benefits associated with the placebo effect exist, but do not alter the pathophysiology of the diseases, only their symptomatic manifestations. For example, there is no evidence that placebos can reduce the size of a tumour. However, clinical trials demonstrate the efficacy of placebos to alleviate the more frequent symptoms of cancer and decrease the side effects produced by chemotherapy, such as fatigue, nausea, hot flashes and pain.Placebo effect and biasWhen we administer a drug or an intervention, there are many variables that can influence the clinical improvement of a patient. We have talked about the placebo effect, but we must assess other phenomena that also act as biases. These phenomena may confuse us and we could be attributing to the placebo effect responses that are unrelated.<a class="elsevierStyleCrossRef" href="#bib0335">7</a>Hawthorne effectThe act of participating in a clinical trial may produce an improvement in symptoms due to the observations the patient receives from the investigators. The Hawthorne effect was described in the 1920s. After years of work, researchers at a Chicago plant (USA) concluded that part of the benefit observed in the workers’ production was due to the fact that they were being studied, rather than to the effect of the production process being implemented.<a class="elsevierStyleCrossRef" href="#bib0340">8</a>Regression to the meanIn statistics, regression to the mean is the phenomenon in which if a variable is extreme in its first measurement, it will tend to be closer to the mean in its second measurement. Regression to the mean is closely related to the natural history of some diseases that occur with variations or exacerbations.<a class="elsevierStyleCrossRef" href="#bib0345">9</a> Patients affected by chronic pain due to musculoskeletal disorders are a good example. These patients usually ask for help when they are experimenting an acute exacerbation. Thus, in subsequent observations, the patient is more likely to be better off, to abandon one of the extremes and return to the mean.Natural course of the diseaseAll diseases have a natural course that includes spontaneous remissions and fluctuations in symptomatology. It is an important bias to attribute these changes to the treatment or the placebo effect.<a class="elsevierStyleCrossRef" href="#bib0350">10</a>Rosenthal effectAlso, known as the Pygmalion effect, it was described by R. Rosenthal in 1963. A person's beliefs and expectations about another individual affect his/her behaviour to such an extent that the latter tends to confirm them. A very close relationship is generated between the researchers and the participants of a study. There is a great commitment on the part of patients with what is expected of them in terms of results. This is the basis of the Pygmalion effect, which psychology explains as a principle of action based on the expectations of others.Other biasesThere are other biases that may affect the internal validity of the studies and raise doubts about the authenticity of the placebo responses. In clinical epidemiology, bias is a deviation from truth. Unlike random errors, bias represents a systematic distortion that can be minimized through rigorous and creative designs. In studies on the placebo effect, we highlight (a) biases due to the selection of participants; (b) biases for cointerventions: patients who do not receive treatment usually look for procedures outside the study protocol more often than patients in the placebo group. This bias may underestimate the placebo response; (c) biases for patient withdrawal: usually, withdrawal affects more patients who belong to the group without intervention; (d) biases produced by the informed consent: a cross-over trial was designed to determine whether the informed consent can modify the analgesic effect of naproxen and placebo. The difference in therapeutic activity between naproxen and placebo was moderately higher in uninformed patients. Information can increase both the apparent efficacy of the drug and that of placebo, and decrease the perceived difference between the two,<a class="elsevierStyleCrossRef" href="#bib0355">11</a> and (e) the publication bias studies with significant results are more frequently published than studies with no differences between groups.<a class="elsevierStyleCrossRef" href="#bib0360">12</a> Clinical trials with positive results are published more often and more rapidly than clinical trials with negative results.<a class="elsevierStyleCrossRef" href="#bib0365">13</a>At present, the placebo effect has staunch advocates, granting it, in many diseases or conditions, an impact similar to the effect of active ingredients. But some authors, led by the Danish author Hróbjartsson, believe that the placebo effect is overrated and that creative and rigorous clinical trials are needed to reduce bias. Studies should compare a placebo intervention group to a non-intervention group. These studies would demonstrate the true effect of placebo interventions and investigate the elements involved in the placebo response.<a class="elsevierStyleCrossRef" href="#bib0305">1</a> In <a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1–3</a>, we can see how the design of a clinical trial may overestimate the placebo effect or the results due to treatment.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Context and placebo effectResearch in neuroscience has shown that the placebo effect is a real biological phenomenon, due to the psychosocial context present in every therapeutic encounter.The quantitative magnitude of the placebo effect was demonstrated in studies of postoperative dental pain.<a class="elsevierStyleCrossRefs" href="#bib0370">14,15</a> Patients were informed that they were being given a painkiller, when in fact they only received a saline solution. The study showed that this placebo was as effective as an intravenous dose of 6–8mg of morphine administered blindly. For the patient, the sight and presence of a physician injecting a supposed analgesic was a potent analgesic in itself. These studies were pioneers in the blind-open label experimental design, which has since been widely used to study the placebo effect.<a class="elsevierStyleCrossRefs" href="#bib0380">16–18</a>In the open label option, the patient who has a parenteral medication route clearly observes how a real analgesic is administered. In the blind option, the same analgesic is also administered by the same route, but through an infusion pump, without the presence of the doctor and without the patient knowing the moment of administration. If patient improvement is solely due to the active ingredient, there should be no difference between the open label and the blind option. It is a creative way of isolating the effects produced solely by the drug from the effects produced by adding the drug and the context variables. Studies in this regard show that the overall effect of the open label administration of a drug to treat anxiety, pain, depression and Parkinson's disease is always superior to the administration of the drug in a blind way.<a class="elsevierStyleCrossRef" href="#bib0395">19</a>In daily clinical practice, the therapeutic effect produced by many treatments is inseparable from the context in which it is administered. Therefore, in addition to the active ingredient there is the placebo effect. The key is to use the components that trigger placebo responses for the benefit of the patient. The placebo effect may enhance the effect of the active ingredient.The interaction between the patient and the therapist is possibly the most important psychosocial factor in the generation of the placebo response.In a clinical trial on the efficacy of placebo acupuncture in patients with irritable bowel disease, different types of physician–patient relationships were researched. The group with a good physician-patient interaction obtained as good results as any medication approved for this disease by the Food and Drug Administration (US Government Agency responsible for drug and food regulation).<a class="elsevierStyleCrossRef" href="#bib0400">20</a>Type of intervention and placebo effectThe type of intervention may influence the placebo response.<a class="elsevierStyleCrossRef" href="#bib0405">21</a> When comparing 2 placebo tablets, if one bears the brand of some well-known pharmaceutical laboratories and the other is administered unbranded, the results in the reduction of pain are superior for the branded placebo tablet. Differences have also been found in the results when comparisons include differences in colour, shape<a class="elsevierStyleCrossRefs" href="#bib0410">22,23</a> or price<a class="elsevierStyleCrossRefs" href="#bib0330">6,24</a> in placebo tablets.In a randomized crossover trial of patients with severe or moderate Parkinson, 2 equal placebos (saline injection) were compared. Motor function and activation of cortical areas were assessed by functional magnetic resonance imaging. Placebo labelled as novel and expensive was more effective in improving motor function than placebo labelled as novel and inexpensive.Some placebo interventions produce higher placebo effects than others. When comparing a placebo pill with a placebo machine that simulates acupuncture, the analgesic results are superior in favour of the machine.<a class="elsevierStyleCrossRef" href="#bib0425">25</a>In the prevention of migraine, a systematic review shows that sham surgery and sham acupuncture have a higher placebo response than orally administered placebo.<a class="elsevierStyleCrossRef" href="#bib0430">26</a>In a cross-over trial, it was shown that the same person responds differently to different types of placebo (placebo tablet or sham acupuncture). The response to placebo is a complex phenomenon that has many variables and goes beyond the characteristics of the patient. This may explain the difficulty of detecting a pattern for “placebo responders”.<a class="elsevierStyleCrossRef" href="#bib0435">27</a>Expectations and conditioningFrom a psychological point of view, the placebo effect can be explained by two mechanisms: expectancy and classical conditioning. Expectation is defined as the reasonable possibility that something will occur, the hope of achieving something. It is a conscious cognitive process involving a desire for relief and a positive anticipation of treatment.<a class="elsevierStyleCrossRefs" href="#bib0440">28,29</a> But it can also involve negative anticipation in the form of anxiety, fear or repulsion. In this case, it is called “nocebo effect”.There is evidence that an improvement in the patient's expectations positively and significantly influences clinical outcomes. Words used by health professionals can have repercussions on the patient's expectations. For example, accompanying a placebo with the phrase “this is a potent analgesic” results in analgesia.<a class="elsevierStyleCrossRef" href="#bib0450">30</a>Adding verbal information to a placebo condition increases patient expectancy and results in increased neuronal activity in areas involved in memory and semantic processing. These areas can influence the areas of the brain involved in emotions and analgesia. Adding verbal information significantly decreases the activity of brain areas that process pain.Learning from information that comes from experts has a great impact on our decision making, creating prejudices difficult to change. Conditioning is a type of learning through which two episodes are associated. It is a process of prediction that can be conscious or unconscious. Classical conditioning, also called Pavlovian conditioning or stimulus-response model, is a type of associative learning that was first demonstrated by I. Pavlov (1849–1936), and developed by J. Watson (1878–1958).An example is found in chemotherapy, in cancer patients; anticipated nausea and vomiting are frequently experienced side effects as a result of chemotherapy. The prevalence ranges from 10% to 63%.<a class="elsevierStyleCrossRef" href="#bib0455">31</a> Even with antiemetic treatments, the prevalence can reach 59%.<a class="elsevierStyleCrossRef" href="#bib0460">32</a> These effects may be partly attributed to a conditioned nocebo effect.<a class="elsevierStyleCrossRef" href="#bib0465">33</a> Conditioning is built by matching different contextual stimuli (e.g., an odour present in the clinical environment) with the nausea and vomiting resulting from chemotherapy.<a class="elsevierStyleCrossRef" href="#bib0470">34</a>This nocebo response could be a learning phenomenon mediated by conditioning mechanisms, and it could be reconstructed again through a technique called overshadowing.<a class="elsevierStyleCrossRef" href="#bib0475">35</a> This technique consists of generating a new positive conditioning relationship through a sweet drink. Patients who received this technique showed less anticipatory nausea and vomiting than those in the control group.<a class="elsevierStyleCrossRef" href="#bib0480">36</a>This type of conditioning, based on components of the psychosocial context, can be a very useful tool from a therapeutic point of view. When a placebo is given for the first time as a substitute for a drug, the placebo effect may appear. But the placebo effect is superior when the placebo is given to a patient who has previously experienced the benefits of the actual drug. If a placebo is given after 2 previously effective experiences with an actual analgesic drug, the placebo effect is much higher.<a class="elsevierStyleCrossRef" href="#bib0485">37</a>Anatomy and physiology of the placebo effectThe 3 main analgesic neurotransmitters that have been related to the neurobiological mechanisms involved in the generation of the placebo effect are: endogenous opiates, dopamine and cannabinoids.Endogenous opioids and cannabinoids are involved in expectancy and conditioning.<a class="elsevierStyleCrossRef" href="#bib0490">38</a> Dopamine is present in the mechanisms of motivation, expectancy and reward. Cannabinoids are involved in non-opioid-mediated placebo-controlled, placebo analgesia.<a class="elsevierStyleCrossRef" href="#bib0495">39</a> The higher the expectations of analgesia, the higher the release of these neurotransmitters and the higher the analgesia experienced. Most neurobiological models for the study of placebo response have been constructed from studies on pain and Parkinson's disease.<a class="elsevierStyleCrossRefs" href="#bib0500">40–42</a>Two meta-analyses on clinical trials with antidepressants showed that patients with placebo responses release endogenous opioids, dopamine and cannabinoids, and activate the serotonergic pathways.<a class="elsevierStyleCrossRefs" href="#bib0515">43,44</a> Oxytocin<a class="elsevierStyleCrossRefs" href="#bib0525">45,46</a> and nitric oxide<a class="elsevierStyleCrossRef" href="#bib0535">47</a> have also been postulated as possible mediators of the placebo response. In the early studies, the relationship between opioids and expectancy was demonstrated pharmacologically. The placebo effect could be completely or partially annulled by naloxone, an opioid antagonist. This fact demonstrated the participation of endogenous opioids in placebo analgesia.<a class="elsevierStyleCrossRefs" href="#bib0540">48,49</a>Neuroimaging techniques, such as functional magnetic resonance imaging and positron emission tomography, have made possible to know the areas involved in placebo analgesia. A meta-analysis, from 25 neuroimaging studies, analysed expectancy-mediated placebo analgesia. It demonstrated that there is a reduction of activity in regions related to pain management, such as the thalamus, insular cortex and amygdala. In other regions, there is an increase in activity when there is positive expectancy of decreased pain, such as, for example, the prefrontal cortex, the middle brain surrounding the periaqueductal grey matter, and the rostral anterior cingulate cortex.<a class="elsevierStyleCrossRef" href="#bib0550">50</a>A placebo may influence the activation of brain regions involved in affective processing and in the cognitive control of emotions. It has been shown that a placebo can modulate the activity of the primary visual cortex, decreasing its interaction with the amygdala and the insular cortex.<a class="elsevierStyleCrossRef" href="#bib0555">51</a> The amygdala is involved in the placebo effect and in the regulation of emotions,<a class="elsevierStyleCrossRef" href="#bib0560">52</a> thus, cortical networks involved in placebo analgesia are largely superimposed on networks involved in the regulation of emotional processes.<a class="elsevierStyleCrossRef" href="#bib0565">53</a> Neuroimaging techniques have also confirmed, on the one hand, the relationship between expectancy and the release of endogenous opioids,<a class="elsevierStyleCrossRef" href="#bib0570">54</a> and on the other, that the pathways selected are the same ones used by pharmacological (exogenous) opioids.<a class="elsevierStyleCrossRef" href="#bib0575">55</a>Motivation and reward use dopaminergic pathways. Its relationship with expectation was based on an intracranial study, where dopamine was released in the nucleus accumbens.<a class="elsevierStyleCrossRef" href="#bib0580">56</a> Dopamine is the main neurotransmitter in reward mechanisms.<a class="elsevierStyleCrossRef" href="#bib0585">57</a> Placebos that promise an expected reward for pain relief produce, first, a release of dopamine in the nucleus accumbens, and subsequently, a release of opioids in the nucleus accumbens itself, in the ventral putamen (responsible for associative learning), the dorsolateral prefrontal cortex, the amygdala, and the posterior and anterior insular cortex. These last 3 structures are related to the limbic system and participate in the control of basic emotions.<a class="elsevierStyleCrossRef" href="#bib0500">40</a>The endocannabinoids also play a role in the placebo effect. These are pathways different from those of opioids and, therefore, the analgesic benefit is not reversed by the administration of naloxone. The role of cannabinoid type 1 receptors has been demonstrated. Their activation is also responsible for the psychoactive effects of tetrahydrocannabinol consumption, active ingredient of the marijuana plant and hashish resin.<a class="elsevierStyleCrossRef" href="#bib0495">39</a>Recently, it has been confirmed that placebo analgesia is mediated by cortical modulation and not by the inhibition of nociceptive sensory inputs in the spine, as initially believed.<a class="elsevierStyleCrossRef" href="#bib0590">58</a>A greater understanding of the neurobiological and genetic mechanisms influencing the placebo effect is essential for the evaluation of health interventions.Nocebo effectNocebo, like placebo, is defined as an inert treatment with no therapeutic properties. Nocebo effect is the negative response produced by the administration of a nocebo. Like the placebo effect, the nocebo effect is generated by the context. The term nocebo was introduced by W. Kennedy in 1961.Negative expectancy in the form of fear and anxiety can generate a nocebo effect. There is evidence that proves that informing about painful interventions increases the intensity of perceived pain. The line separating appropriate information from excessive information is very thin.Through an open-blind design, it was shown that when a patient openly sees the interruption of the analgesic infusion of morphine or diazepam, the pain appears more quickly and is of greater intensity than when it is interrupted in a hidden way.<a class="elsevierStyleCrossRef" href="#bib0595">59</a>The nocebo effect should be taken into account in the interpretation of adverse effects reported in clinical trials.Other factors that may influence the placebo responseThe magnitude of the placebo effect depends on the variables of the clinical trial and its design; for example, the randomization ratio. The 4:1 ratio (for every 4 patients assigned to the active ingredient one will be assigned to the placebo group) has a greater placebo effect than the 3:1 and 2:1 ratios. The lowest placebo response was obtained in the 1:1 ratio. When the drug used in the clinical trial is an opioid, greater placebo responses are obtained than when a non-opioid drug is used. The higher the number of scheduled control visits, the higher the magnitude of the placebo effect; for example, 8 follow-up visits versus 5. However, the type of active ingredient, the randomization ratio and the scheduled control visits represent only 10% of the variability in placebo responses. Therefore, it can be concluded that most of the placebo effect is due to individual factors not yet identified.<a class="elsevierStyleCrossRef" href="#bib0600">60</a> There is a growing interest in determining the individual factors that can predict the placebo response.Future lines of researchResearch on the placebo effect has focused on two main areas: knowledge of the neurobiological mechanisms activated after the administration of a placebo and the analysis of the situations in which the placebo response occurs.Most of the knowledge about placebo and nocebo responses has been achieved through studies with healthy volunteers and designs that deviate from usual clinical practice. Although the neuroscience that supports the placebo effect is extensive, there is a deficit in clinical research that explores, in healthcare settings, the context and placebo responses that accompany any therapeutic intervention.Creative thinking and research must go hand in hand to design studies that rigorously identify the elements involved in the placebo effect and determine their role in clinical outcomes.The relationship between the patient and the therapist is possibly the most important factor in the generation of placebo and nocebo responses. Additionally, the therapist's communicative abilities could reinforce the properties of the drug or the intervention applied.Future clinical trials that study the context of patient–therapist relationships should be designed to differentiate placebo and nocebo responses from other confounding phenomena, such as regression to the mean, the natural course of disease or non-specific benefits of the patient's participation in a study. Not taking these factors into account would lead to an overestimation of placebo and nocebo responses.ConclusionsIn short, more research is needed on the contextual elements that influence placebo and nocebo effects. These are real biological phenomena with important implications for clinical practice, whose context includes numerous symbols and signals that are interpreted by the patient and can alter the treatments’ efficacy. However, the potential of this overlap has not yet been sufficiently studied. The challenge is exciting; increasing the knowledge in this field will improve interactions between health professionals and patients.Conflict of interestsThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres872653" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec861388" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres872652" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec861389" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Definition" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Placebo effect and bias" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Hawthorne effect" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Regression to the mean" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Natural course of the disease" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Rosenthal effect" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Other biases" ] ] ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Context and placebo effect" ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Type of intervention and placebo effect" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Expectations and conditioning" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Anatomy and physiology of the placebo effect" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Nocebo effect" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "Other factors that may influence the placebo response" ] 12 => array:2 [ "identificador" => "sec0070" "titulo" => "Future lines of research" ] 13 => array:2 [ "identificador" => "sec0075" "titulo" => "Conclusions" ] 14 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interests" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-03-14" "fechaAceptado" => "2017-03-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec861388" "palabras" => array:3 [ 0 => "Placebo effect" 1 => "Nocebo effect" 2 => "Therapeutic context" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec861389" "palabras" => array:3 [ 0 => "Efecto placebo" 1 => "Efecto nocebo" 2 => "Contexto terapéutico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "When we apply a physical or pharmacological treatment, there are many things that may explain the clinical improvement experienced by a patient. The drugs or physical agents applied are important, but we must also add other elements in the context of the patient–therapist relationship. Scientific evidence has proven that the placebo effect exists. This is a true biopsychosocial phenomenon produced by the context in which an intervention is carried out. Biases aside, placebo and nocebo responses are changes in patients’ symptoms, due to their participation at the therapeutic meeting, with its rituals, symbols and interactions. This multitude of signals inherent, in any intervention, is perceived and interpreted by patients and can create positive or negative expectations." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Cuando administramos un tratamiento físico o farmacológico, existen muchas variables que pueden explicar la mejoría clínica que experimenta un paciente. El principio activo del fármaco o el agente físico aplicado son importantes, pero también hay que sumarle otros elementos presentes en el contexto de la relación paciente-terapeuta. La evidencia científica ha demostrado que el efecto placebo existe. Se trata de un auténtico fenómeno biopsicosocial producido por el contexto en el cual se lleva a cabo una intervención. Sesgos al margen, las respuestas placebo y nocebo son cambios en los síntomas de los pacientes atribuibles a su participación en el encuentro terapéutico, con sus rituales, símbolos e interacciones. Esta multitud de señales inherentes a toda intervención son percibidas e interpretadas por los pacientes, generando expectativas positivas o negativas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Morral A, Urrutia G, Bonfill X. Efecto placebo y contexto terapéutico: un reto en investigación clínica. Med Clin (Barc). 2017;149:26–31." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1323 "Ancho" => 1718 "Tamanyo" => 119282 ] ] "descripcion" => array:1 [ "en" => "A clinical trial with 3 groups (treated, placebo and untreated) allows to differentiate the results due to the treatment, the therapeutic context and those produced by the participation of a patient in a study." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1309 "Ancho" => 1689 "Tamanyo" => 84525 ] ] "descripcion" => array:1 [ "en" => "If the clinical trial does not have an “untreated” group, the placebo effect will be overestimated." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1386 "Ancho" => 1732 "Tamanyo" => 99827 ] ] "descripcion" => array:1 [ "en" => "If the clinical trial does not have a placebo group, the treatment results we will be overestimated." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The silent healer: the role of communication in placebo effects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.M. 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Placebo effect and therapeutic context: A challenge in clinical research

Efecto placebo y contexto terapéutico: un reto en investigación clínica

Antoni Morrala,

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antonimf@blanquerna.url.edu
antonifm@blanquerna.url.edu

Corresponding author.

, Gerard Urrutiab, Xavier Bonfillb

a Facultat de Ciències de la Salut Blanquerna, Universitat Ramon Llull, Barcelona, Spain

b Centro Cochrane Iberoamericano, Institut d’Investigació Biomèdica, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Definition</span><p id="par0005" class="elsevierStylePara elsevierViewall">The word <span class="elsevierStyleItalic">placebo</span> and the expression <span class="elsevierStyleItalic">placebo effect</span> have different meanings&#46; Placebo means an inert treatment&#44; without therapeutic properties&#46; Placebo effect is the response produced by the administration of a placebo&#46; Placebo effect and placebo response are equivalent&#46; These definitions contain a great paradox&#58; How is it possible that something inert generates a response&#63; If something is inert&#44; by definition&#44; it is incapable of producing responses&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The word <span class="elsevierStyleItalic">placebo</span> is a conjugation of the Latin verb <span class="elsevierStyleItalic">placere</span>&#44; which means to please&#44; to gratify&#44; to satisfy&#46; The placebo effect appeared with force in the scientific community after World War II&#44; following Henry Beecher&#39;s article &#8220;The powerful placebo&#8221; published in the <span class="elsevierStyleItalic">JAMA</span> journal&#44; in 1955&#46; Beecher treated soldiers that had been wounded during the war&#46; He observed that in some of them&#44; the pain could be mitigated with a saline solution and that this produced effects similar to morphine&#46; Thirty-five percent of patients responded positively to placebo treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Beecher&#39;s work on placebo was the beginning of medicine&#39;s modern era&#44; where the randomized clinical trial represents the gold standard for evaluating the efficacy of an intervention&#46; However&#44; Beecher overestimated the placebo effect because it did not differentiate it from other bias or confounding factors&#44; such as&#44; for example&#44; the natural course of the disease or regression to the mean&#46; Since then there has been a growing interest in researching the placebo effect&#44; especially in the last 15 years&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In a broad sense&#44; the placebo effect refers to improvements in the symptoms of patients that are attributable to their participation in a therapeutic encounter&#44; with its rituals&#44; symbols and interactions&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The patient&#8211;therapist relationship implies a therapeutic ritual composed of a multitude of signs and symbols that are consciously and unconsciously perceived&#46; These perceived messages are interpreted by patients&#44; generating expectancy and conditioning&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> We emphasize verbal and non-verbal communication&#44; empathy&#44; touch&#44; gaze&#44; enthusiasm&#44; predisposition to listen and respond&#44; trust&#44; diagnostic and therapeutic tools&#44; technology use&#44; office or hospital room appearance&#44; appearance of the waiting room&#44; the white dressing gown&#44; the stethoscope and the type of intervention &#40;a pill or a physical agent&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> This context is always present when a patient is subject to an intervention&#44; whether we administer a tablet containing sugar or a tablet containing a potent analgesic&#46; The tablet may be inert but the context is not&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The placebo effect is based on complex neurobiological mechanisms involving neurotransmitters &#40;e&#46;g&#46; endorphins&#44; cannabinoids and dopamine&#41; and the activation of specific and quantifiable areas of the brain&#58; the prefrontal cortex&#44; the anterior insular cortex&#44; the rostral anterior cingulate cortex&#44; and the amygdala&#44; areas related to anticipation and reward&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5&#44;6</span></a> Many drugs also act through these pathways&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Recently&#44; genes that predispose to a higher placebo response are being identified&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Current evidence shows that the therapeutic benefits associated with the placebo effect exist&#44; but do not alter the pathophysiology of the diseases&#44; only their symptomatic manifestations&#46; For example&#44; there is no evidence that placebos can reduce the size of a tumour&#46; However&#44; clinical trials demonstrate the efficacy of placebos to alleviate the more frequent symptoms of cancer and decrease the side effects produced by chemotherapy&#44; such as fatigue&#44; nausea&#44; hot flashes and pain&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Placebo effect and bias</span><p id="par0045" class="elsevierStylePara elsevierViewall">When we administer a drug or an intervention&#44; there are many variables that can influence the clinical improvement of a patient&#46; We have talked about the placebo effect&#44; but we must assess other phenomena that also act as biases&#46; These phenomena may confuse us and we could be attributing to the placebo effect responses that are unrelated&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Hawthorne effect</span><p id="par0050" class="elsevierStylePara elsevierViewall">The act of participating in a clinical trial may produce an improvement in symptoms due to the observations the patient receives from the investigators&#46; The Hawthorne effect was described in the 1920s&#46; After years of work&#44; researchers at a Chicago plant &#40;USA&#41; concluded that part of the benefit observed in the workers&#8217; production was due to the fact that they were being studied&#44; rather than to the effect of the production process being implemented&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Regression to the mean</span><p id="par0055" class="elsevierStylePara elsevierViewall">In statistics&#44; regression to the mean is the phenomenon in which if a variable is extreme in its first measurement&#44; it will tend to be closer to the mean in its second measurement&#46; Regression to the mean is closely related to the natural history of some diseases that occur with variations or exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Patients affected by chronic pain due to musculoskeletal disorders are a good example&#46; These patients usually ask for help when they are experimenting an acute exacerbation&#46; Thus&#44; in subsequent observations&#44; the patient is more likely to be better off&#44; to abandon one of the extremes and return to the mean&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Natural course of the disease</span><p id="par0060" class="elsevierStylePara elsevierViewall">All diseases have a natural course that includes spontaneous remissions and fluctuations in symptomatology&#46; It is an important bias to attribute these changes to the treatment or the placebo effect&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Rosenthal effect</span><p id="par0065" class="elsevierStylePara elsevierViewall">Also&#44; known as the Pygmalion effect&#44; it was described by R&#46; Rosenthal in 1963&#46; A person&#39;s beliefs and expectations about another individual affect his&#47;her behaviour to such an extent that the latter tends to confirm them&#46; A very close relationship is generated between the researchers and the participants of a study&#46; There is a great commitment on the part of patients with what is expected of them in terms of results&#46; This is the basis of the Pygmalion effect&#44; which psychology explains as a principle of action based on the expectations of others&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Other biases</span><p id="par0070" class="elsevierStylePara elsevierViewall">There are other biases that may affect the internal validity of the studies and raise doubts about the authenticity of the placebo responses&#46; In clinical epidemiology&#44; bias is a deviation from truth&#46; Unlike random errors&#44; bias represents a systematic distortion that can be minimized through rigorous and creative designs&#46; In studies on the placebo effect&#44; we highlight &#40;a&#41; <span class="elsevierStyleItalic">biases due to the selection of participants</span>&#59; &#40;b&#41; <span class="elsevierStyleItalic">biases for cointerventions</span>&#58; patients who do not receive treatment usually look for procedures outside the study protocol more often than patients in the placebo group&#46; This bias may underestimate the placebo response&#59; &#40;c&#41; <span class="elsevierStyleItalic">biases for patient withdrawal</span>&#58; usually&#44; withdrawal affects more patients who belong to the group without intervention&#59; &#40;d&#41; <span class="elsevierStyleItalic">biases produced by the informed consent</span>&#58; a cross-over trial was designed to determine whether the informed consent can modify the analgesic effect of naproxen and placebo&#46; The difference in therapeutic activity between naproxen and placebo was moderately higher in uninformed patients&#46; Information can increase both the apparent efficacy of the drug and that of placebo&#44; and decrease the perceived difference between the two&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> and &#40;e&#41; the <span class="elsevierStyleItalic">publication bias</span> studies with significant results are more frequently published than studies with no differences between groups&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">12</span></a> Clinical trials with positive results are published more often and more rapidly than clinical trials with negative results&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">At present&#44; the placebo effect has staunch advocates&#44; granting it&#44; in many diseases or conditions&#44; an impact similar to the effect of active ingredients&#46; But some authors&#44; led by the Danish author Hr&#243;bjartsson&#44; believe that the placebo effect is overrated and that creative and rigorous clinical trials are needed to reduce bias&#46; Studies should compare a placebo intervention group to a non-intervention group&#46; These studies would demonstrate the true effect of placebo interventions and investigate the elements involved in the placebo response&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> In <a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1&#8211;3</a>&#44; we can see how the design of a clinical trial may overestimate the placebo effect or the results due to treatment&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Context and placebo effect</span><p id="par0080" class="elsevierStylePara elsevierViewall">Research in neuroscience has shown that the placebo effect is a real biological phenomenon&#44; due to the psychosocial context present in every therapeutic encounter&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The quantitative magnitude of the placebo effect was demonstrated in studies of postoperative dental pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">14&#44;15</span></a> Patients were informed that they were being given a painkiller&#44; when in fact they only received a saline solution&#46; The study showed that this placebo was as effective as an intravenous dose of 6&#8211;8<span class="elsevierStyleHsp" style=""></span>mg of morphine administered blindly&#46; For the patient&#44; the sight and presence of a physician injecting a supposed analgesic was a potent analgesic in itself&#46; These studies were pioneers in the blind-open label experimental design&#44; which has since been widely used to study the placebo effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#8211;18</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In the open label option&#44; the patient who has a parenteral medication route clearly observes how a real analgesic is administered&#46; In the blind option&#44; the same analgesic is also administered by the same route&#44; but through an infusion pump&#44; without the presence of the doctor and without the patient knowing the moment of administration&#46; If patient improvement is solely due to the active ingredient&#44; there should be no difference between the open label and the blind option&#46; It is a creative way of isolating the effects produced solely by the drug from the effects produced by adding the drug and the context variables&#46; Studies in this regard show that the overall effect of the open label administration of a drug to treat anxiety&#44; pain&#44; depression and Parkinson&#39;s disease is always superior to the administration of the drug in a blind way&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In daily clinical practice&#44; the therapeutic effect produced by many treatments is inseparable from the context in which it is administered&#46; Therefore&#44; in addition to the active ingredient there is the placebo effect&#46; The key is to use the components that trigger placebo responses for the benefit of the patient&#46; The placebo effect may enhance the effect of the active ingredient&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The interaction between the patient and the therapist is possibly the most important psychosocial factor in the generation of the placebo response&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In a clinical trial on the efficacy of placebo acupuncture in patients with irritable bowel disease&#44; different types of physician&#8211;patient relationships were researched&#46; The group with a good physician-patient interaction obtained as good results as any medication approved for this disease by the <span class="elsevierStyleItalic">Food and Drug Administration</span> &#40;US Government Agency responsible for drug and food regulation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Type of intervention and placebo effect</span><p id="par0110" class="elsevierStylePara elsevierViewall">The type of intervention may influence the placebo response&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> When comparing 2 placebo tablets&#44; if one bears the brand of some well-known pharmaceutical laboratories and the other is administered unbranded&#44; the results in the reduction of pain are superior for the branded placebo tablet&#46; Differences have also been found in the results when comparisons include differences in colour&#44; shape<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">22&#44;23</span></a> or price<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;24</span></a> in placebo tablets&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In a randomized crossover trial of patients with severe or moderate Parkinson&#44; 2 equal placebos &#40;saline injection&#41; were compared&#46; Motor function and activation of cortical areas were assessed by functional magnetic resonance imaging&#46; Placebo labelled as novel and expensive was more effective in improving motor function than placebo labelled as novel and inexpensive&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Some placebo interventions produce higher placebo effects than others&#46; When comparing a placebo pill with a placebo machine that simulates acupuncture&#44; the analgesic results are superior in favour of the machine&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In the prevention of migraine&#44; a systematic review shows that sham surgery and sham acupuncture have a higher placebo response than orally administered placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In a cross-over trial&#44; it was shown that the same person responds differently to different types of placebo &#40;placebo tablet or sham acupuncture&#41;&#46; The response to placebo is a complex phenomenon that has many variables and goes beyond the characteristics of the patient&#46; This may explain the difficulty of detecting a pattern for &#8220;placebo responders&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Expectations and conditioning</span><p id="par0135" class="elsevierStylePara elsevierViewall">From a psychological point of view&#44; the placebo effect can be explained by two mechanisms&#58; expectancy and classical conditioning&#46; Expectation is defined as the reasonable possibility that something will occur&#44; the hope of achieving something&#46; It is a conscious cognitive process involving a desire for relief and a positive anticipation of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">28&#44;29</span></a> But it can also involve negative anticipation in the form of anxiety&#44; fear or repulsion&#46; In this case&#44; it is called &#8220;nocebo effect&#8221;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">There is evidence that an improvement in the patient&#39;s expectations positively and significantly influences clinical outcomes&#46; Words used by health professionals can have repercussions on the patient&#39;s expectations&#46; For example&#44; accompanying a placebo with the phrase &#8220;this is a potent analgesic&#8221; results in analgesia&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Adding verbal information to a placebo condition increases patient expectancy and results in increased neuronal activity in areas involved in memory and semantic processing&#46; These areas can influence the areas of the brain involved in emotions and analgesia&#46; Adding verbal information significantly decreases the activity of brain areas that process pain&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Learning from information that comes from experts has a great impact on our decision making&#44; creating prejudices difficult to change&#46; Conditioning is a type of learning through which two episodes are associated&#46; It is a process of prediction that can be conscious or unconscious&#46; Classical conditioning&#44; also called Pavlovian conditioning or stimulus-response model&#44; is a type of associative learning that was first demonstrated by <span class="elsevierStyleSmallCaps">I</span>&#46; Pavlov &#40;1849&#8211;1936&#41;&#44; and developed by J&#46; Watson &#40;1878&#8211;1958&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">An example is found in chemotherapy&#44; in cancer patients&#59; anticipated nausea and vomiting are frequently experienced side effects as a result of chemotherapy&#46; The prevalence ranges from 10&#37; to 63&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> Even with antiemetic treatments&#44; the prevalence can reach 59&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a> These effects may be partly attributed to a conditioned nocebo effect&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a> Conditioning is built by matching different contextual stimuli &#40;e&#46;g&#46;&#44; an odour present in the clinical environment&#41; with the nausea and vomiting resulting from chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">This nocebo response could be a learning phenomenon mediated by conditioning mechanisms&#44; and it could be reconstructed again through a technique called <span class="elsevierStyleItalic">overshadowing</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> This technique consists of generating a new positive conditioning relationship through a sweet drink&#46; Patients who received this technique showed less anticipatory nausea and vomiting than those in the control group&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">This type of conditioning&#44; based on components of the psychosocial context&#44; can be a very useful tool from a therapeutic point of view&#46; When a placebo is given for the first time as a substitute for a drug&#44; the placebo effect may appear&#46; But the placebo effect is superior when the placebo is given to a patient who has previously experienced the benefits of the actual drug&#46; If a placebo is given after 2 previously effective experiences with an actual analgesic drug&#44; the placebo effect is much higher&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Anatomy and physiology of the placebo effect</span><p id="par0170" class="elsevierStylePara elsevierViewall">The 3 main analgesic neurotransmitters that have been related to the neurobiological mechanisms involved in the generation of the placebo effect are&#58; endogenous opiates&#44; dopamine and cannabinoids&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Endogenous opioids and cannabinoids are involved in expectancy and conditioning&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a> Dopamine is present in the mechanisms of motivation&#44; expectancy and reward&#46; Cannabinoids are involved in non-opioid-mediated placebo-controlled&#44; placebo analgesia&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> The higher the expectations of analgesia&#44; the higher the release of these neurotransmitters and the higher the analgesia experienced&#46; Most neurobiological models for the study of placebo response have been constructed from studies on pain and Parkinson&#39;s disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">40&#8211;42</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Two meta-analyses on clinical trials with antidepressants showed that patients with placebo responses release endogenous opioids&#44; dopamine and cannabinoids&#44; and activate the serotonergic pathways&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">43&#44;44</span></a> Oxytocin<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">45&#44;46</span></a> and nitric oxide<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> have also been postulated as possible mediators of the placebo response&#46; In the early studies&#44; the relationship between opioids and expectancy was demonstrated pharmacologically&#46; The placebo effect could be completely or partially annulled by naloxone&#44; an opioid antagonist&#46; This fact demonstrated the participation of endogenous opioids in placebo analgesia&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">48&#44;49</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Neuroimaging techniques&#44; such as functional magnetic resonance imaging and positron emission tomography&#44; have made possible to know the areas involved in placebo analgesia&#46; A meta-analysis&#44; from 25 neuroimaging studies&#44; analysed expectancy-mediated placebo analgesia&#46; It demonstrated that there is a reduction of activity in regions related to pain management&#44; such as the thalamus&#44; insular cortex and amygdala&#46; In other regions&#44; there is an increase in activity when there is positive expectancy of decreased pain&#44; such as&#44; for example&#44; the prefrontal cortex&#44; the middle brain surrounding the periaqueductal grey matter&#44; and the rostral anterior cingulate cortex&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">A placebo may influence the activation of brain regions involved in affective processing and in the cognitive control of emotions&#46; It has been shown that a placebo can modulate the activity of the primary visual cortex&#44; decreasing its interaction with the amygdala and the insular cortex&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a> The amygdala is involved in the placebo effect and in the regulation of emotions&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> thus&#44; cortical networks involved in placebo analgesia are largely superimposed on networks involved in the regulation of emotional processes&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a> Neuroimaging techniques have also confirmed&#44; on the one hand&#44; the relationship between expectancy and the release of endogenous opioids&#44;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> and on the other&#44; that the pathways selected are the same ones used by pharmacological &#40;exogenous&#41; opioids&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Motivation and reward use dopaminergic pathways&#46; Its relationship with expectation was based on an intracranial study&#44; where dopamine was released in the nucleus accumbens&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a> Dopamine is the main neurotransmitter in reward mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> Placebos that promise an expected reward for pain relief produce&#44; first&#44; a release of dopamine in the nucleus accumbens&#44; and subsequently&#44; a release of opioids in the nucleus accumbens itself&#44; in the ventral putamen &#40;responsible for associative learning&#41;&#44; the dorsolateral prefrontal cortex&#44; the amygdala&#44; and the posterior and anterior insular cortex&#46; These last 3 structures are related to the limbic system and participate in the control of basic emotions&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">The endocannabinoids also play a role in the placebo effect&#46; These are pathways different from those of opioids and&#44; therefore&#44; the analgesic benefit is not reversed by the administration of naloxone&#46; The role of cannabinoid type 1 receptors has been demonstrated&#46; Their activation is also responsible for the psychoactive effects of tetrahydrocannabinol consumption&#44; active ingredient of the marijuana plant and hashish resin&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Recently&#44; it has been confirmed that placebo analgesia is mediated by cortical modulation and not by the inhibition of nociceptive sensory inputs in the spine&#44; as initially believed&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">A greater understanding of the neurobiological and genetic mechanisms influencing the placebo effect is essential for the evaluation of health interventions&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Nocebo effect</span><p id="par0215" class="elsevierStylePara elsevierViewall">Nocebo&#44; like placebo&#44; is defined as an inert treatment with no therapeutic properties&#46; Nocebo effect is the negative response produced by the administration of a nocebo&#46; Like the placebo effect&#44; the nocebo effect is generated by the context&#46; The term <span class="elsevierStyleItalic">nocebo</span> was introduced by W&#46; Kennedy in 1961&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Negative expectancy in the form of fear and anxiety can generate a nocebo effect&#46; There is evidence that proves that informing about painful interventions increases the intensity of perceived pain&#46; The line separating appropriate information from excessive information is very thin&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Through an open-blind design&#44; it was shown that when a patient openly sees the interruption of the analgesic infusion of morphine or diazepam&#44; the pain appears more quickly and is of greater intensity than when it is interrupted in a hidden way&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">The nocebo effect should be taken into account in the interpretation of adverse effects reported in clinical trials&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Other factors that may influence the placebo response</span><p id="par0235" class="elsevierStylePara elsevierViewall">The magnitude of the placebo effect depends on the variables of the clinical trial and its design&#59; for example&#44; the randomization <span class="elsevierStyleItalic">ratio</span>&#46; The 4&#58;1 <span class="elsevierStyleItalic">ratio</span> &#40;for every 4 patients assigned to the active ingredient one will be assigned to the placebo group&#41; has a greater placebo effect than the 3&#58;1 and 2&#58;1 <span class="elsevierStyleItalic">ratios</span>&#46; The lowest placebo response was obtained in the 1&#58;1 <span class="elsevierStyleItalic">ratio</span>&#46; When the drug used in the clinical trial is an opioid&#44; greater placebo responses are obtained than when a non-opioid drug is used&#46; The higher the number of scheduled control visits&#44; the higher the magnitude of the placebo effect&#59; for example&#44; 8 follow-up visits versus 5&#46; However&#44; the type of active ingredient&#44; the randomization <span class="elsevierStyleItalic">ratio</span> and the scheduled control visits represent only 10&#37; of the variability in placebo responses&#46; Therefore&#44; it can be concluded that most of the placebo effect is due to individual factors not yet identified&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a> There is a growing interest in determining the individual factors that can predict the placebo response&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Future lines of research</span><p id="par0240" class="elsevierStylePara elsevierViewall">Research on the placebo effect has focused on two main areas&#58; knowledge of the neurobiological mechanisms activated after the administration of a placebo and the analysis of the situations in which the placebo response occurs&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Most of the knowledge about placebo and nocebo responses has been achieved through studies with healthy volunteers and designs that deviate from usual clinical practice&#46; Although the neuroscience that supports the placebo effect is extensive&#44; there is a deficit in clinical research that explores&#44; in healthcare settings&#44; the context and placebo responses that accompany any therapeutic intervention&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Creative thinking and research must go hand in hand to design studies that rigorously identify the elements involved in the placebo effect and determine their role in clinical outcomes&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">The relationship between the patient and the therapist is possibly the most important factor in the generation of placebo and nocebo responses&#46; Additionally&#44; the therapist&#39;s communicative abilities could reinforce the properties of the drug or the intervention applied&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Future clinical trials that study the context of patient&#8211;therapist relationships should be designed to differentiate placebo and nocebo responses from other confounding phenomena&#44; such as regression to the mean&#44; the natural course of disease or non-specific benefits of the patient&#39;s participation in a study&#46; Not taking these factors into account would lead to an overestimation of placebo and nocebo responses&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusions</span><p id="par0265" class="elsevierStylePara elsevierViewall">In short&#44; more research is needed on the contextual elements that influence placebo and nocebo effects&#46; These are real biological phenomena with important implications for clinical practice&#44; whose context includes numerous symbols and signals that are interpreted by the patient and can alter the treatments&#8217; efficacy&#46; However&#44; the potential of this overlap has not yet been sufficiently studied&#46; The challenge is exciting&#59; increasing the knowledge in this field will improve interactions between health professionals and patients&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflict of interests</span><p id="par0270" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "identificador" => "xres872653"
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          "titulo" => "Keywords"
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          "identificador" => "sec0005"
          "titulo" => "Definition"
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          "identificador" => "sec0010"
          "titulo" => "Placebo effect and bias"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Hawthorne effect"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Regression to the mean"
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            2 => array:2 [
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              "titulo" => "Natural course of the disease"
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              "identificador" => "sec0030"
              "titulo" => "Rosenthal effect"
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              "identificador" => "sec0035"
              "titulo" => "Other biases"
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        6 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Context and placebo effect"
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        7 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Type of intervention and placebo effect"
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        8 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Expectations and conditioning"
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          "titulo" => "Anatomy and physiology of the placebo effect"
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          "titulo" => "Nocebo effect"
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          "titulo" => "Other factors that may influence the placebo response"
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    "fechaRecibido" => "2017-03-14"
    "fechaAceptado" => "2017-03-28"
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            2 => "Therapeutic context"
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            0 => "Efecto placebo"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">When we apply a physical or pharmacological treatment&#44; there are many things that may explain the clinical improvement experienced by a patient&#46; The drugs or physical agents applied are important&#44; but we must also add other elements in the context of the patient&#8211;therapist relationship&#46; Scientific evidence has proven that the placebo effect exists&#46; This is a true biopsychosocial phenomenon produced by the context in which an intervention is carried out&#46; Biases aside&#44; placebo and nocebo responses are changes in patients&#8217; symptoms&#44; due to their participation at the therapeutic meeting&#44; with its rituals&#44; symbols and interactions&#46; This multitude of signals inherent&#44; in any intervention&#44; is perceived and interpreted by patients and can create positive or negative expectations&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cuando administramos un tratamiento f&#237;sico o farmacol&#243;gico&#44; existen muchas variables que pueden explicar la mejor&#237;a cl&#237;nica que experimenta un paciente&#46; El principio activo del f&#225;rmaco o el agente f&#237;sico aplicado son importantes&#44; pero tambi&#233;n hay que sumarle otros elementos presentes en el contexto de la relaci&#243;n paciente-terapeuta&#46; La evidencia cient&#237;fica ha demostrado que el efecto placebo existe&#46; Se trata de un aut&#233;ntico fen&#243;meno biopsicosocial producido por el contexto en el cual se lleva a cabo una intervenci&#243;n&#46; Sesgos al margen&#44; las respuestas placebo y nocebo son cambios en los s&#237;ntomas de los pacientes atribuibles a su participaci&#243;n en el encuentro terap&#233;utico&#44; con sus rituales&#44; s&#237;mbolos e interacciones&#46; Esta multitud de se&#241;ales inherentes a toda intervenci&#243;n son percibidas e interpretadas por los pacientes&#44; generando expectativas positivas o negativas&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Morral A&#44; Urrutia G&#44; Bonfill X&#46; Efecto placebo y contexto terap&#233;utico&#58; un reto en investigaci&#243;n cl&#237;nica&#46; Med Clin &#40;Barc&#41;&#46; 2017&#59;149&#58;26&#8211;31&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A clinical trial with 3 groups &#40;treated&#44; placebo and untreated&#41; allows to differentiate the results due to the treatment&#44; the therapeutic context and those produced by the participation of a patient in a study&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">If the clinical trial does not have an &#8220;untreated&#8221; group&#44; the placebo effect will be overestimated&#46;</p>"
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                      "titulo" => "The silent healer&#58; the role of communication in placebo effects"
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                          "autores" => array:2 [
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                      "doi" => "10.1016/j.pec.2010.05.033"
                      "Revista" => array:6 [
                        "tituloSerie" => "Patient Educ Couns"
                        "fecha" => "2010"
                        "volumen" => "80"
                        "paginaInicial" => "293"
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