Should we consider the indication of placebo in clinical practice?

Dalmau Llitjos, A.
doi:10.1016/j.redare.2021.11.007
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The placebo effect &#40;derived from the Latin &#34;placere&#34;&#44; meaning pleasure&#44; to like&#44; to please&#41; and nocebo &#40;derived from the Latin &#34;nocere&#34;&#44; meaning to harm&#44; to hurt&#44; to injure&#41; are sensations of positive or negative expectations&#44; based on prior knowledge&#44; that the patient has related to their state of health and conditioned by their own or others&#39; experience&#44; so that the higher the expectation&#44; the more powerful the effect and its future conditioning&#46; Both effects can occur when receiving information&#44; receiving a treatment or participating in a study&#46; For several decades&#44; placebo studies have shown neurobiological and clinical responses after administration of an inert substance in different diseases such as irritable bowel syndrome&#44; chronic low back pain&#44; neoplastic fatigue&#44; migraine&#44; pruritus and depression&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In recent years&#44; a number of reviews have been published that have argued the benefit of the clinical use of placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;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&#44; placebo was used as a non-specific treatment in medical practice&#46; During World War II&#44; Beecher&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> using an analytical method&#44; described the percentage of patients who improved satisfactorily with the administration of a placebo in 15 clinical trials&#46; He also considered the total effect of a drug to be equal to its active effect plus the placebo effect&#44; a consideration that has been little taken into account&#46; Since then&#44; randomised&#44; 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&#44; so that the medical intervention is only scientifically accepted if it is superior to the placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Medical evidence therefore excludes the placebo effect of any active substance&#44; despite the fact that many double-blind studies show similar efficacy between the drug studied and the placebo&#44; e&#46;g&#46; in pain&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Moreover&#44; their use is not accepted in clinical practice&#46; However&#44; Fassler et al&#46; conducted a systematic review of 22 studies in 12 different countries and found that 17&#37;&#8211;80&#37; of the clinicians questioned had administered placebo as a treatment in the form of sugar capsules or saline injections during their practice&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Furthermore&#44; regardless of the treatment&#44; the doctor-patient interaction influences the likelihood of placebo and nocebo effects&#46; Clinical practice has taught us that the physician not only helps the patient by administering specific drugs and procedures&#44; but that a good relationship between the two&#44; based on trust and positive and open communication&#44; facilitates the process of healing or symptom control&#44; as well as the clinician&#39;s positive expectations playing a role in the placebo effect&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Conversely&#44; worrying information&#44; erroneous beliefs&#44; pessimistic expectations&#44; previously negative experiences and an unempathic relationship hinder the healing process and promote anxiety and the occurrence of side effects&#46;</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&#44; such as those by Amanzio and Benedetti<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> have shown the release of neurotransmitters &#40;endorphins&#44; dopamine and cannabinoids&#41; with placebo administration&#46; 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&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Furthermore&#44; there are several functional neuroimaging studies&#44; such as those reported in the very recent meta-analysis by Zunhammer et al&#46;&#44;<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&#44; especially in patients with a significant placebo response&#46; Both the molecular events and neural network changes triggered by the placebo effect appear to be related to expectations and anticipation of outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> However&#44; there are randomised studies&#44; in which the patient is aware of the administration of placebo vs&#46; conventional treatment&#44; in which a significant improvement in symptoms has been observed in patients who were given placebo in different processes&#44; such as chronic low back pain&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and in these studies many patients had no expectations&#44; which suggests that not all of the placebo effect can be explained by conditioning and expectation&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">As Colloca and Barsky point out&#44; some expectations&#44; the placebo and nocebo effect are not consciously accessible&#44; for example&#44; the possibility of conditioning an immunosuppressive response by administering a neutral stimulus previously linked to an immunosuppressive drug in kidney transplant patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;11</span></a> This conditioned reflex has also been observed in other clinical situations&#44; such as the administration of morphine together with another stimulus and the subsequent replacement of morphine by placebo&#58; in both cases&#44; an analgesic effect was achieved&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Very interesting are the studies by Benedetti et al&#46; showing that the replacement of morphine&#44; after repeated doses&#44; 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&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> an effect that Colloca et al&#46;<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&#46; In the review they conclude that the use of placebo as an extension of a pharmacological effect&#44; in an acceptable ethical framework&#44; could be part of the therapeutic arsenal&#58; it preserves beneficial effects&#44; reduces costs and side effects and&#44; possibly&#44; dependence and tolerance&#44; although confirmatory studies of safety&#44; feasibility and optimisation of the reduction dose would be necessary first&#46;</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&#44; as it is related to the knowledge or beliefs that both have on the subject&#44; ethical considerations and the doctor-patient relationship&#46; Based on the clinician&#39;s principle of beneficence&#44; the patient&#39;s lack of knowledge and the patient&#39;s right to be informed&#44; a dilemma can arise in the management of placebo in the clinical setting&#46; The way to resolve it is to offer transparent information based on current knowledge and potential benefit&#44; exploring and working on the expectations of each individual patient &#40;fears&#44; doubts&#44; previous experiences&#41;&#44; positively reinforcing its administration and accepting withdrawal in the event of worsening or not obtaining the expected benefit&#46; In this regard&#44; the study by Kisaalita et al&#46;<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&#46; In an open study by Carvalho et al&#46;&#44;<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&#46;</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&#58;<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&#46;</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&#44; in addition to the placebo&#44; in order to discern the beneficial effect of the intervention studied&#44; subtracting the placebo effect&#46;</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&#44; within an ethical framework&#44; the possibility of administering a placebo in diseases in which it has been shown to be beneficial&#44; with a specific record of its prescription&#44; with follow-up and control of results until there are more studies confirming this research&#46;</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&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5</span><p id="par0060" class="elsevierStylePara elsevierViewall">As clinicians&#44; it is our responsibility and reflection to consider and concede the possibility of treatments that provide benefits and minimise risks&#46;</p></li></ul></p></span></span>"
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