Editorial article
Should we consider the indication of placebo in clinical practice?
¿Se debería plantear la indicación del placebo en la práctica clínica?
A. Dalmau Llitjos
Unidad de Dolor Agudo, Servicio de Anestesiología y Reanimación, Hospital Universitario de Bellvitge, Barcelona, Spain
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"apellidos" => "Dalmau Llitjos" "email" => array:1 [ 0 => "madalmau@bellvitgehospital.cat" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Dolor Agudo, Servicio de Anestesiología y Reanimación, Hospital Universitario de Bellvitge, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Se debería plantear la indicación del placebo en la práctica clínica?" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The placebo effect (derived from the Latin "placere", meaning pleasure, to like, to please) and nocebo (derived from the Latin "nocere", meaning to harm, to hurt, to injure) are sensations of positive or negative expectations, based on prior knowledge, that the patient has related to their state of health and conditioned by their own or others' experience, so that the higher the expectation, the more powerful the effect and its future conditioning. Both effects can occur when receiving information, receiving a treatment or participating in a study. For several decades, placebo studies have shown neurobiological and clinical responses after administration of an inert substance in different diseases such as irritable bowel syndrome, chronic low back pain, neoplastic fatigue, migraine, pruritus and depression.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In recent years, a number of reviews have been published that have argued the benefit of the clinical use of placebo.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Origen of the interest in the placebo effect</span><p id="par0010" class="elsevierStylePara elsevierViewall">In the past, placebo was used as a non-specific treatment in medical practice. During World War II, Beecher,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> using an analytical method, described the percentage of patients who improved satisfactorily with the administration of a placebo in 15 clinical trials. He also considered the total effect of a drug to be equal to its active effect plus the placebo effect, a consideration that has been little taken into account. Since then, randomised, double-blind studies have been imposed as the objective method of scientific study and the placebo has acquired value as a comparative element without taking into account its effect, so that the medical intervention is only scientifically accepted if it is superior to the placebo.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Medical evidence therefore excludes the placebo effect of any active substance, despite the fact that many double-blind studies show similar efficacy between the drug studied and the placebo, e.g. in pain.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Moreover, their use is not accepted in clinical practice. However, Fassler et al. conducted a systematic review of 22 studies in 12 different countries and found that 17%–80% of the clinicians questioned had administered placebo as a treatment in the form of sugar capsules or saline injections during their practice.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Furthermore, regardless of the treatment, the doctor-patient interaction influences the likelihood of placebo and nocebo effects. Clinical practice has taught us that the physician not only helps the patient by administering specific drugs and procedures, but that a good relationship between the two, based on trust and positive and open communication, facilitates the process of healing or symptom control, as well as the clinician's positive expectations playing a role in the placebo effect.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Conversely, worrying information, erroneous beliefs, pessimistic expectations, previously negative experiences and an unempathic relationship hinder the healing process and promote anxiety and the occurrence of side effects.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Some scientific research studies on the placebo effect</span><p id="par0020" class="elsevierStylePara elsevierViewall">Several studies, such as those by Amanzio and Benedetti<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> have shown the release of neurotransmitters (endorphins, dopamine and cannabinoids) with placebo administration. They also found that the induction of the nocebo effect by verbal suggestion is mediated by the neuropeptide cholecystokinin<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and blocked by proglumide.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Furthermore, there are several functional neuroimaging studies, such as those reported in the very recent meta-analysis by Zunhammer et al.,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> which have found that placebo treatment affects activity in thalamo-cortical pathways related to nociception and pain, especially in patients with a significant placebo response. Both the molecular events and neural network changes triggered by the placebo effect appear to be related to expectations and anticipation of outcome.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> However, there are randomised studies, in which the patient is aware of the administration of placebo vs. conventional treatment, in which a significant improvement in symptoms has been observed in patients who were given placebo in different processes, such as chronic low back pain,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and in these studies many patients had no expectations, which suggests that not all of the placebo effect can be explained by conditioning and expectation.</p><p id="par0025" class="elsevierStylePara elsevierViewall">As Colloca and Barsky point out, some expectations, the placebo and nocebo effect are not consciously accessible, for example, the possibility of conditioning an immunosuppressive response by administering a neutral stimulus previously linked to an immunosuppressive drug in kidney transplant patients.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,11</span></a> This conditioned reflex has also been observed in other clinical situations, such as the administration of morphine together with another stimulus and the subsequent replacement of morphine by placebo: in both cases, an analgesic effect was achieved.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Very interesting are the studies by Benedetti et al. showing that the replacement of morphine, after repeated doses, by placebo produced a potent analgesic effect that was reversed with naloxone<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and was long-lasting,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> an effect that Colloca et al.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> call dose-extending placebos in a review on the conditioning and prolongation of the analgesic effect with placebo. In the review they conclude that the use of placebo as an extension of a pharmacological effect, in an acceptable ethical framework, could be part of the therapeutic arsenal: it preserves beneficial effects, reduces costs and side effects and, possibly, dependence and tolerance, although confirmatory studies of safety, feasibility and optimisation of the reduction dose would be necessary first.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Indication of the placebo effect</span><p id="par0030" class="elsevierStylePara elsevierViewall">The indication of placebo is seen from different points of view by both health professionals and patients, as it is related to the knowledge or beliefs that both have on the subject, ethical considerations and the doctor-patient relationship. Based on the clinician's principle of beneficence, the patient's lack of knowledge and the patient's right to be informed, a dilemma can arise in the management of placebo in the clinical setting. The way to resolve it is to offer transparent information based on current knowledge and potential benefit, exploring and working on the expectations of each individual patient (fears, doubts, previous experiences), positively reinforcing its administration and accepting withdrawal in the event of worsening or not obtaining the expected benefit. In this regard, the study by Kisaalita et al.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> showed that patients who were informed of the benefit of a placebo had better acceptance and benefit in the treatment of chronic pain than those who did not receive the instruction. In an open study by Carvalho et al.,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> they observed that placebo administration improved pain and disability in patients with low back pain.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Considerations</span><p id="par0035" class="elsevierStylePara elsevierViewall">All of the above leads us to a series of considerations:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0040" class="elsevierStylePara elsevierViewall">It is essential to establish a relationship with the patient to favour the placebo effect and avoid the nocebo effect in order to facilitate the process of healing or symptom control.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0045" class="elsevierStylePara elsevierViewall">The inclusion of a non-interventionist group in scientific research should be considered, in addition to the placebo, in order to discern the beneficial effect of the intervention studied, subtracting the placebo effect.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3</span><p id="par0050" class="elsevierStylePara elsevierViewall">Consideration should be given to including in the therapeutic arsenal, within an ethical framework, the possibility of administering a placebo in diseases in which it has been shown to be beneficial, with a specific record of its prescription, with follow-up and control of results until there are more studies confirming this research.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4</span><p id="par0055" class="elsevierStylePara elsevierViewall">The important benefit for patients receiving more toxic or addictive drugs of administering placebo after active drug conditioning should be estimated if further studies are conducted to confirm these results.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5</span><p id="par0060" class="elsevierStylePara elsevierViewall">As clinicians, it is our responsibility and reflection to consider and concede the possibility of treatments that provide benefits and minimise risks.</p></li></ul></p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Origen of the interest in the placebo effect" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Some scientific research studies on the placebo effect" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Indication of the placebo effect" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Considerations" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Placebo and nocebo effects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L. 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