Better than nothing: A historical account of placebos and placebo effects from modern to contemporary medicine.

Throughout the history of medicine, multiple conceptions of "placebo" and "placebo effect" have often co-existed across different domains, and today the meaning of these concepts is still disputed. Against this background, this chapter provides a succinct account of the key events in the history of the concepts of "placebo," "placebo control," and "placebo effect." The first section reconstructs the etymology of the term "placebo" and its first introduction in medicine. The next sections provide an account of how placebos have been employed in both medical practice and scientific research in modern medicine. Later sections trace the emergence of the concepts of "placebo control" and "placebo effect" in the first half of the 20th century, from the first empirical studies investigating the effects of placebos up to the publication of Beecher's landmark article "The Powerful Placebo." Finally, the last two sections review the varieties of randomized, placebo-controlled trials (RCTs) in the second half of the 20th century, and the subsequent wave of empirical studies that, starting from the 1970s, have investigated the psychological, pharmacological and neurobiological mechanisms of placebo effects.

Placebo Effects: Historical and Modern Evaluation.

The history of the placebo phenomenon is both interesting and informative. The placebo effect is a core component of health care, and if one considers a contemporary view of placebo effects, this has likely been the case for as long as records exist. An exploration of placebos and placebo effects across several centuries demonstrates many interesting facts, ranging from very early writings and experiments to the modern investigation of placebo mechanisms. A longitudinal review reveals the many challenges that have been faced, whether this is understanding what a placebo is, why it may work, and the meaning of such responses for routine clinical practice. At the core of this process are the concepts surrounding placebo, as these are imperative in the application of placebo to both routine clinical care and in the context of clinical trial design. This narrative review will look at the history of placebo, particularly key aspects over time, with a view to presenting a modern re-conceptualization of this field so as to facilitate ongoing scientific inquiry and to improve health care.

50th anniversary of the Declaration of Helsinki: the double standard was introduced.

The Declaration of Helsinki (DoH), adopted by the World Medical Association (WMA), is one of the most influential international documents in research ethics, is turning 50 in 2014. Its regular updates, seven versions (1975, 1983, 1989, 1996, 2000, 2008, 2013) and two notes of clarification (2002, 2004), characterize it as a 'live' document. The seventh version of the DoH was amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. The new version was reorganized and restructured, with paragraphs subdivided and regrouped. However, the DoH remains controversial and some ethical issues are still uncovered. The major problem was the insertion of the phrase 'less effective than the best proven' on placebo paragraph in order to allow double standard in medical research in low-resource countries. The DoH is a 'live' document, which will continually have to deal with new topics and challenges. Health equity needs to be a priority, and with that, a single ethical standard for medical research.

El placebo y el efecto placebo / Placebo and placebo effect

Se denomina placebo a una intervención diseñada para simular una terapia médica, que no tiene efectos específicos para la condición que está siendo aplicada. El efecto placebo es la modificación, muchas veces fisiológicamente demostrable, que se produce en el organismo como resultado del estímulo psicológico inducido por la administración de una sustancia inerte, de un fármaco o de un tratamiento. En este trabajo se abordan las definiciones de placebo, el origen de este término, los factores y mecanismos que intervienen en el efecto placebo, así como el uso de los placebos en la práctica médica y en la investigación clínica(AU)

Placebo is an intervention designed to simulate a medical therapy, which has no specific effects for the condition that is being applied. The placebo effect is the change, often physiologically provable, which is produced in the body as a result of a psychological stimulus induced by the administration of an inert substance, a drug or a treatment. We hereby include the definition of placebo, the origin of this word, the factors and mechanisms involved in the placebo effect, and the use of placebos in medical practice and clinical research(AU)

El placebo y el efecto placebo / Placebo and placebo effect

Se denomina placebo a una intervención diseñada para simular una terapia médica, que no tiene efectos específicos para la condición que está siendo aplicada. El efecto placebo es la modificación, muchas veces fisiológicamente demostrable, que se produce en el organismo como resultado del estímulo psicológico inducido por la administración de una sustancia inerte, de un fármaco o de un tratamiento. En este trabajo se abordan las definiciones de placebo, el origen de este término, los factores y mecanismos que intervienen en el efecto placebo, así como el uso de los placebos en la práctica médica y en la investigación clínica...

Placebo is an intervention designed to simulate a medical therapy, which has no specific effects for the condition that is being applied. The placebo effect is the change, often physiologically provable, which is produced in the body as a result of a psychological stimulus induced by the administration of an inert substance, a drug or a treatment. We hereby include the definition of placebo, the origin of this word, the factors and mechanisms involved in the placebo effect, and the use of placebos in medical practice and clinical research...

Clinical research before informed consent.

Clinical research with patient-subjects was routinely conducted without informed consent for research participation prior to 1966. The aim of this article is to illuminate the moral climate of clinical research at this time, with particular attention to placebo-controlled trials in which patient-subjects often were not informed that they were participating in research or that they might receive a placebo intervention rather than standard medical treatment or an experimental treatment for their condition. An especially valuable window into the thinking of clinical investigators about their relationship with patient-subjects in the era before informed consent is afforded by reflection on two articles published by psychiatric researchers in 1966 and 1967, at the point of transition between clinical research conducted under the guise of medical care and clinical research based on consent following an invitation to participate and disclosure of material information about the study. Historical inquiry relating to the practice of clinical research without informed consent helps to put into perspective the moral progress associated with soliciting consent following disclosure of pertinent information; it also helps to shed light on an important issue in contemporary research ethics: the conditions under which it is ethical to conduct clinical research without informed consent.

Placebo and nocebo effect: a mini-review.

It is well-known that placebo is a substance without medical effects, which benefits the health status because of the patient's belief that the substance is effective and that the nocebo is defined as a substance without medical effects but which worsenes the health status of the person taking it by the negative beliefs and expectations of the patient. Starting with the history of the placebo effect and giving a review of the most significant studies reporting about the placebo effect from 1939-2013 it was our intention to give the all-around look on this phenomena discussing the neurobiological and other theories of its origin and concentrating especially on the field of psychiatry and finally coming to conclusions regarding the conductance of clinical trials and ethics. Regarding psychiatry, the placebo effect has a substantial role in most of psychiatric conditions including depression, anxiety, addictions, and contrary to what may have been expected, schizophrenia. Likewise, the nocebo effect is not to be neglected as the studies are being conducted to identify the factors causing it so it could be prevented.

Hahnemann and placebo.

Samuel Hahnemann (1755-1843) known today as the founder of homoeopathy, was - as far as we know - the first physician who administrated placebos to his patient on a systematic and regular basis. This study is based upon unpublished documents (e.g. patients' letters) in the Archives of the Institute for the History of Medicine of the Robert Bosch Foundation in Stuttgart. It also profited from the critical edition of Hahnemann's case journals and the editorial comments which have also been published in this series. Hahnemann differentiated clearly between homeopathic drugs and pharmaceutical substances which he considered as sham medicine (e.g. milk sugar). A close look at Hahnemann's case journals reveals that the percentage of placebo prescriptions was very high (between 54 and 85 percent). In most instances Hahnemann marked placebos with the paragraph symbol (§). The rationale behind this practice was that Hahnemann had encountered the well-known problem that patients were used to taking medicine on a daily basis as it was typical for the age of heroic medicine. The main reason for giving placebo was therefore to please the impatient patient who was used to frequent medications in allopathic medicine, not only every day but sometimes also hourly.

Placebo: la ®mancha¼ más brillante de la Medicina / Placebo: the brightest ®spot¼ in medicine

Introducción: quizás ningún otro término haya sido tan indebidamente utilizado y causado tanta confusión como ®placebo¼. Sus efectos han potenciado los tratamientos médicos en la historia sin el debido reconocimiento. Entendido como eventos atribuibles al significado que adquiere una intervención dentro de un contexto terapéutico dado, se redimensiona y aleja de las definiciones tautológicas dominantes. Objetivo: analizar los retos que esta postura teórica plantea, así como sus potencialidades para la investigación y la práctica clínica. Métodos: Se analizan las limitaciones de su uso en Ensayos Clínicos Aleatorizados, entre las que se destaca la paradoja de la eficacia. Se contrasta la evidencia sobre su efectividad, generada en distintos contextos. Se describen los placebos disponibles en la práctica clínica y situaciones de uso; así como las opiniones de médicos y pacientes. Se introduce su efecto desde la dimensión biopsicosocial, dentro de la Medicina del Estilo de Vida. Se esbozan razones que impiden a las medicinas alternativas ®ser mejor que un placebo¼. Por último, se identifica y ejemplifica su espacio dentro la práctica clínica. Conclusiones: el efecto del placebo debe ser comprendido como un efecto del contexto, estructurado sobre la base del significado individual asignado a la intervención dentro de una cultura e historia específicas, que resulta significativo sobre numerosas enfermedades, mediante la activación y modificación variables psicológicas y fisiológicas. Concebido como Ambiente Curativo Óptimo, adquiere el ®principio activo¼ necesario para actuar por sí mismo (cuando la alternativa es no hacer nada), o potenciando el efecto de los tratamientos convencionales(AU)

Introduction: no term has probably been as misused and has caused so much confusion as the term `placebo'. Its effects have strengthened medical treatments throughout history without receiving due recognition. Understood as events attributable to the significance acquired by an intervention in a given therapeutic context, it takes on a new dimension, detaching from the prevailing tautological definitions. Objective: analyze the challenges posed by this theoretical stand, as well as its potential for research and clinical practice. Method: an analysis is conducted of the limitations of its use in randomized clinical trials, among them the efficacyparadox. A contrast is made of evidence of its effectiveness generated in various contexts. A description is provided of placebos available in clinical practice and situations of use, as well as doctors' and patients' opinions. Its effect is presented from a biopsychosocial perspective, within the framework of Lifestyle Medicine. An outline is provided of the factors preventing alternative medicines from being ®better than a placebo¼. Finally, its place in clinical practice is identified and exemplified. Conclusions: the placebo effect should be understood as an effect from the context, structured on the basis of the individual significance assigned to the intervention by a specific culture and historical development, which is significant for a large number of diseases, through the activation and modification of psychological and physiological variables. Conceived of as an Optimal Healing Environment, it acquires the ®active principle¼ required to act by itself (when the alternative is doing nothing), or strengthen the effect of conventional treatments(AU)

Placebo: la ®mancha» más brillante de la Medicina / Placebo: the brightest ®spot» in medicine

Introducción: quizás ningún otro término haya sido tan indebidamente utilizado y causado tanta confusión como ®placebo». Sus efectos han potenciado los tratamientos médicos en la historia sin el debido reconocimiento. Entendido como eventos atribuibles al significado que adquiere una intervención dentro de un contexto terapéutico dado, se redimensiona y aleja de las definiciones tautológicas dominantes. Objetivo: analizar los retos que esta postura teórica plantea, así como sus potencialidades para la investigación y la práctica clínica. Métodos: Se analizan las limitaciones de su uso en Ensayos Clínicos Aleatorizados, entre las que se destaca la paradoja de la eficacia. Se contrasta la evidencia sobre su efectividad, generada en distintos contextos. Se describen los placebos disponibles en la práctica clínica y situaciones de uso; así como las opiniones de médicos y pacientes. Se introduce su efecto desde la dimensión biopsicosocial, dentro de la Medicina del Estilo de Vida. Se esbozan razones que impiden a las medicinas alternativas ®ser mejor que un placebo». Por último, se identifica y ejemplifica su espacio dentro la práctica clínica. Conclusiones: el efecto del placebo debe ser comprendido como un efecto del contexto, estructurado sobre la base del significado individual asignado a la intervención dentro de una cultura e historia específicas, que resulta significativo sobre numerosas enfermedades, mediante la activación y modificación variables psicológicas y fisiológicas. Concebido como Ambiente Curativo Óptimo, adquiere el ®principio activo» necesario para actuar por sí mismo (cuando la alternativa es no hacer nada), o potenciando el efecto de los tratamientos convencionales

Introduction: no term has probably been as misused and has caused so much confusion as the term `placebo'. Its effects have strengthened medical treatments throughout history without receiving due recognition. Understood as events attributable to the significance acquired by an intervention in a given therapeutic context, it takes on a new dimension, detaching from the prevailing tautological definitions. Objective: analyze the challenges posed by this theoretical stand, as well as its potential for research and clinical practice. Method: an analysis is conducted of the limitations of its use in randomized clinical trials, among them the efficacyparadox. A contrast is made of evidence of its effectiveness generated in various contexts. A description is provided of placebos available in clinical practice and situations of use, as well as doctors' and patients' opinions. Its effect is presented from a biopsychosocial perspective, within the framework of Lifestyle Medicine. An outline is provided of the factors preventing alternative medicines from being ®better than a placebo». Finally, its place in clinical practice is identified and exemplified. Conclusions: the placebo effect should be understood as an effect from the context, structured on the basis of the individual significance assigned to the intervention by a specific culture and historical development, which is significant for a large number of diseases, through the activation and modification of psychological and physiological variables. Conceived of as an Optimal Healing Environment, it acquires the ®active principle» required to act by itself (when the alternative is doing nothing), or strengthen the effect of conventional treatments

The early history of the placebo.

In the late 18th century the term "placebo" became part of medical jargon. In contrast to the prevailing opinion that it was the Scottish physician and pharmacologist William Cullen (1710-1790) who introduced this expression into medical language in 1772, the credit must be given to another English physician, Alexander Sutherland (born before 1730 - died after 1773). The main reason for administering placebos in late 18th-century medical practice was to satisfy the patient's demand and his expectations. Another reason was obstinancy of the patient: the motivation behind such prescriptions may be summarized as prescribing inert drugs for the satisfaction of the patient's mind, and not with the view of producing any direct remedial effect. In most cases these 18th century physicians did not administer "pure" placebos but resorted to any kind of medicine which they thought simple, feeble, or altogether powerless, non-perturbing medicines. Today we make the distinction between pure placebos (substances with no pharmacological effect, e.g. sugar pills) and impure placebos (substances with pharmacological effect but not on the condition being treated). In the 18th century those physicians who prescribed placebo usually thought of drugs which were considered not very effective in the particular case, e.g. a mild ointment. At the same time, only very few brilliant minds came up with the ingenious idea of using inert substances as placebo. An alternative to milk sugar used as placebo in homeopathy was breadpills. Recent research suggests that expectancy is an integral part of the placebo effect. As early as 1775 the English bishop John Douglas (1721-1807) anticipated the findings of modern research on the placebo effect.

Placebos in 19th century medicine: a quantitative analysis of the BMJ.

OBJECTIVE: To provide the first quantitative data on the use of the term "placebo" in the 19th century. DESIGN: Computer search of BMJ's archival database from January 1840 (the first issue) through December 1899 for uses of the words "placebo(s)." Grounded theory was used to categorise the implications of uses of the term. RESULTS: 71 citations contained the term "placebo(s)." Of these, 22 (31%) used the term to mean "no effect" or as a general pejorative term, 18 (25%) portrayed placebo treatment as permitting the unfolding of the natural history (the normal waxing and waning of illness), 14 (20%) described placebo as important to satisfy patients, 7 (10%) described it as fulfilling a physician's performance role, 3 (4%) described its use to buy time, 3 (4%) described its use for financial gain, 2 (3%) used it in a manner similar to a placebo control, and only one implied that placebo could have a clinical effect. Only one citation mentioned telling the patient about his placebo treatment. CONCLUSION: Nineteenth century physicians had diverse a priori assumptions about placebos. These findings remind us that contemporary medicine needs to use rigorous science to separate fact from its own beliefs concerning the "provision of care." As in previous generations, ethical issues concerning placebos continue to challenge medicine.

Placebo, a historical perspective.

Substances and interventions with no specific therapeutic effect have been in use since the dawn of history. The term placebo has first been mentioned in the Scriptures, but it was not until the 19th century that it appeared in a medical context. Although lay people like Voltaire, and physicians such as Sir William Osler, have raised the possibility that much of what physicians did had no specific therapeutic effect, this notion was not shared by the public at large or by the medical profession. It was only by the end of the 18th century that a placebo-controlled trial has been conducted, repudiating the therapeutic effect of mesmerism. The advent, in the late 1940s, of effective treatments, which also had serious adverse effects, made the distinction between placebo and putative, active drug effects more relevant and urgent, and cleared the way for double-blind, randomized, placebo-controlled trials. This in turn triggered an ethical debate on the use of placebo, both in research and in clinical practice. Anthropologists, sociologists, physiologists, and medical researchers are all focusing their efforts on understanding the mechanism, role and modulating factors of placebo.

From medicine to psychotherapy: the placebo effect.

If placebos have been squeezed out of medicine to the point where their official place in in clinical trials designed to identify their own confounding effect, the placebo effect nevertheless thrives in psychotherapy. Not only does psychotherapy dispose of placebo effects that are less available to medicine as it becomes increasingly technological and preoccupied with body parts, but factors of the sort inhibiting the use of placebos in medicine have no equivalent in psychology. Medicine today is disturbed by the placebo effect in a way psychotherapy is not. Psychotherapy does not have to grapple with such a disconcerting paradox as successful sham surgery, and unlike those physicians who once pretended to treat the patient's body while actually attempting to treat the mind, the psychotherapist can treat the mind in all frankness. Perhaps it is because psychotherapy is less burdened by doubts about the placebo effect that it was able to come to its aid when it was orphaned by medicine. It is vain to expect something with so long a history as the placebo effect to disappear from the practices of healing.

A brief history of placebos and clinical trials in psychiatry.

The history of placebos in psychiatry can be understood only in the context of randomized controlled trials (RCTs). Placebo treatments are as old as medicine itself, and are particularly effective in dealing with psychosomatic symptoms. In psychiatry, placebos have mainly been featured in clinical drug trials. The earliest controlled trial in psychiatry (not involving drugs) occurred in 1922, followed by the first crossover studies during the 1930s. Meanwhile the concept of randomization was developed during the interwar years by British statistician Ronald A Fisher, and introduced in 3 trials of tuberculosis drugs between 1947 and 1951. These classic studies established the RCT as the gold standard in pharmaceutical trials, and its status was cemented during the mid-1950s. Nevertheless, while the placebo became established as a standard measure of drug action, placebo treatments became stigmatized as unethical. This is unfortunate, as they constitute one of the most powerful therapies in psychiatry. In recent years, moreover, the dogma of the placebo-controlled trial as the only acceptable data for drug licensing is also being increasingly discredited. This backlash has had 2 sources: one is the recognition that the US Food and Drug Administration has been too lax in permitting trials controlled with placebos alone, rather than also using an active agent as a test of comparative efficacy. In addition, there is evidence that in the hands of the pharmaceutical industry, the scientific integrity of RCTs themselves has been degraded into a marketing device. The once-powerful placebo is thus threatened with extinction.