Original Neurosciences and History 2015; 3(2): 68-80 A history of the placebo C. Guijarro Department of Neurology. Hospital La Milagrosa, Madrid, Spain; Hospital Santa Bárbara, Puertollano, Spain. is study was presented at the 66th Annual Meeting of the Spanish Society of Neurology in November 2014 in Valencia. ABSTRACT Background. A placebo is a treatment designed to simulate a medical intervention, but which does not exert a biological effect on the disease in question. The term originates from the Latin for “I shall please”. Centuries of medical practice provide many examples that lead us to ponder whether the history of treatment is actually equivalent to the history of the placebo effect. The main question is whether the total effect of any substance is equal to the sum of the effect of its active ingredient (specific effect) and its placebo effect. Methods and development. is study examines different treatments that have been applied throughout the history of medicine. In contrast with the medicine employed by primitive societies, which is based on magic and religion, modern pharmaceutical treatments always include an active ingredient. Conclusions. e placebo effect is very important in clinical trials, considering that the placebo is the gold standard against which treatments are compared in these studies. Guidelines are needed for both alternative medicine and evidence-based medicine so that the placebo effect can be measured in both cases. KEYWORDS Placebo effect, history of medicine, clinical trials, alternative treatments Introduction once regulations for clinical trials were approved after World War II. A placebo is a treatment designed to simulate a medical intervention, but which does not exert a biological effect This review presents a summary of the numerous treat- on the disease in question. Deriving from Latin, ments used throughout the history of medicine to support ‘placebo’ means “I shall please”. Medicine provides my conviction that the history of medicine and the history many examples that raise the question of whether the of the placebo are one and the same. I place particular history of medical treatment might be considered the emphasis on the placebo effect in clinical trials, given that history of the placebo effect. The Catholic Church the placebo is the gold standard against which treatments popularised the use of placebos in the sixteenth century, are compared in this type of study. And while many to discredit those who performed exorcisms for profit. specific drugs are available, numerous treatments are also The Church’s intent was to show imitations of sacred used as placebos; here, the medicinal effect is provided by relics to those said to be possessed by the devil; if their doctors, since our mere presence is enough to exert a possession seemed to abate, this was proof that it had placebo effect on patients. In the context of the rise of alter- been simulated. The idea spread throughout the medical native medicine, and given the lack of scientific studies that community, and widespread use of harmless substances prove their efficacy in most cases, doctors need guidelines began to be seen in the eighteenth century. The concept to help measure the magnitude of the placebo effect in both of the placebo effect only became officially recognised alternative and evidence-based medicine. Corresponding author: Dr Cristina Guijarro Received: 18 January 2015 / Accepted: 16 February 2015 E-mail: [email protected] © 2015 Sociedad Española de Neurología 68 A history of the placebo Development Furthermore, the effect increases with pill size and number.8,9 We also know that the placebo effect depends Mechanisms of the placebo effect on the cultural context, and that a name-brand placebo It is important to distinguish between placebos them- is more effective than a generic.10 Similarly, expensive selves and the placebo effect.1 Any type of treatment may placebos are more effective than inexpensive ones.11 act as a placebo, and the placebo effect is the patient’s Other studies have established that injections and response to that treatment. It is defined as any effect acupuncture are more effective than pills against pain, produced by the act of taking a treatment, but not by the whereas pills are more effective as hypnotics.12 Further- properties inherent to that treatment.2 The specificity of more, good adherence to a placebo regimen decreases the placebo effect depends on the information the patient mortality due to the healthy adherer effect.13 We also receives and the patient’s resulting expectations for the know that prior experiences modulate the placebo intervention. Certain effects associated with treatment, effect,4 and that the composition of placebos is often not such as quality of care from doctors or nurses and the indicated in clinical trials that may contain biases for14 doctor-patient relationship, may increase the benefits of or against15 active treatment. the treatment.3 Medicine in primitive societies The placebo effect derives from psychological and neurobiological mechanisms. Among other psycholog- The common denominator for medicinal practices in ical mechanisms, patient expectations play a key role.4 primitive societies is that illness was interpreted as divine Recent studies have begun to shed light on some of the punishment, provoked by breaking a taboo or religious biochemical bases of the placebo effect. For example, law, or the work of witches or sorcerers. In any case, whereas placebo-induced analgesia has been linked to illness was regarded as a supernatural occurrence. Both the release of endogenous opioids, placebo-induced diagnosis and treatment of diseases required magical or release of dopamine gives rise to motor improvements religious means and rites, and the people entrusted with in Parkinson’s disease. One theory proposes that the patient care were priests or shamans. Treatment and diag- placebo effect is mediated by the activation of reward nosis also drew from other magical and religious prac- circuits.5 These biochemical findings indicate that the tices, such as observing crystals, throwing bones in the placebo effect is real, and they suggest that many of the air, entering trance states to perform diagnoses, and a arguments and ethical debates revolving around placebo variety of ceremonies, prayers, and magical rituals. use should be reconsidered. Although minimising the Patients were also therapeutically patted and touched placebo effect may be recommendable for clinical trials, with specific objects. in which the goal is to measure the pure effect of the Diseases were understood to arise from different causes. active ingredient and act in the patient’s best interest, Some of the more frequent included divine punishment, the placebo effect is habitually exaggerated in clinical a foreign object such as a stone or bone entering the 6 settings. We know that administration of a placebo patient’s body, possession by a spirit, loss of the soul, the stimulates the prefrontal, orbitofrontal, and anterior ‘evil eye’, and fright. Traumatic lesions, pregnancy compli- cingulate cortices, the nucleus accumbens, amygdala, cations, and even animal bites (from jaguars or snakes, periaqueductal grey, and the spinal cord. The placebo for example), were charged with magical or supernatural effect may translate to physiological changes, such as meaning in the primitive world. pain reduction due to endorphin release, increases in endogenous dopamine in patients with Parkinson’s Nevertheless, medicine in primitive societies was effec- disease, and changes in bronchial muscle tone and tive due to the positive psychological effect of the maximum peak flow in patients with asthma.5 In fact, doctor-patient relationship. The patient and his family studies with positron emission tomography (PET) have and friends, along with the doctor and his helpers, all shown that the placebo effect is similar to that of belonged to the same social context and shared the same opioids, and can be reversed with naloxone. beliefs and ideas about illnesses. Many diseases did run their course naturally, and this spontaneous recovery Evaluations of the placebo effect of different drugs have was fundamentally promoted by the placebo effect. I shown that, generally speaking, warm colours work might also point out that primitive medicine was better as stimulants and cold colours as anxiolytics.7 reasonably effective at treating war wounds and other 69 C. Guijarro traumatic lesions, managing complications of pregnancy ical basis is that life force (Qi) regulates spiritual, and childbirth, and caring for many acute gynaecolog- emotional, mental, and physical balance, and that it is ical and paediatric illnesses. On some occasions, affected by the opposing forces of ‘ying’ (negative however, the treatment provided by the priest or shaman energy) and ‘yang’ (positive energy). Diseases arise was (and continues to be) catastrophic for the patient, when something disrupts the flow of Qi. Chinese medi- owing both to the interventions that were performed cine includes herbal treatments, diets and nutrient and to those omitted. supplementation, physical exercise, meditation, acupuncture and moxibustion, therapeutic massage, Traditional Chinese medicine prescriptions from the Chinese pharmacopoeia, and others. Chinese medicine consists of a catalogue of traditional healing practices developed between the beginning of Acupuncture was the most commonly employed treat- the Common Era and about the year 1600. Its theoret- ment in China during 2500 years. Archaeological Figure 1. Neurochemical consequences of the placebo effect4 70 A history of the placebo research dates the dawn of acupuncture to the Neolithic An important part of an asu’s treatment plan was or Stone Age. A ‘bian’ was a sharp stone for skinning placing little statues of threatening-looking monsters animals, and it was also used in those times to apply around the sick person. This way, the demon causing pressure to different parts of a sick person’s body in an the illness would see them and be frightened off. attempt to alleviate the discomfort in some way.