Placebos and Placebo Effects in Medicine: Historical Overview
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JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 92 October 1999 Placebos and placebo effects in medicine: historical overview Anton J M de Craen PhD Ted J Kaptchuk OMD1 Jan G P Tijssen PhD J Kleijnen MD PhD2 J R Soc Med 1999;92:51 1-515 In modern medical research placebos constitute an PLACEBOS IN CLINICAL PRACTICE BEFORE WORLD WAR 11 important methodological tool. Placebos are given to controls in a clinical trial with the intention of mimicking Until the first half of the 20th century the use of placebos some experimental intervention. Although the most seems to have been widespread in medicine. In 1807 frequently used placebo is the 'sugar pill' in drug trials, Thomas Jefferson, recording what he called the pious fraud, placebos can be and have been used for all kinds of observed that 'one of the most successful physicians I have interventions, ranging from placebo ultrasound in the ever known has assured me that he used more bread pills, treatment of pressure ulcers and placebo surgery in the treat- drops of colored water, and powders of hickory ashes, than ment of osteoarthritis to sham traction in the treatment of of all other medicines put together'4. About a hundred low back pain and placebo oestrogen implants in the years later, Richard Cabot, of Harvard Medical School, prevention of menopause symptoms. described how he 'was brought up, as I suppose every physician is, to use placebo, bread pills, water subcu- taneously, and other devices'5. ETYMOLOGY Only a few physicians considered the bread pill a threat The word placebo (Latin, 'I shall please') was first used in to the integrity of medicine, and most ethical codes the 14th centuryl. In that period, it referred to hired endorsed 'necessary deception'. A 'polychromatic assort- mourners at funerals. These individuals often began their ment of sugar pills' was routinely quaffed by patients6. wailings with Placebo Domino in regione vivorum, the ninth However, placebos were thought to bring only comfort to verse of psalm cxiv, which in the Latin Vulgate translation the patient, with no impact on pathophysiology7. The value means 'I shall please the Lord in the land of the living'. of placebo was thought inversely related to the intelligence Here, the word placebo carries the connotation of of the patient; the use of a medical ritual was more effective depreciation and substitution, because professional mourn- and necessary for 'unintelligent, neurotic, or inadequate ers were often stand-ins for members of the family of the patients'8. deceased. Around the same time, in the late 1 300s, Geoffrey Chaucer in his Canterbury Tales (Merchant's Tale) PLACEBOS IN CLINICAL RESEARCH depicts a man named Placebo. Like the hired mourners, the Until 1950, most therapies were judged to be efficacious on man is associated with wicked behaviour and is portrayed as the basis of pathophysiological rationales provided by a sycophant. authoritative experts rather than by documented observa- The first documented medical use of the word placebo tions and comparative research9. The bulk of clinical dates from the late 18th century1. In the 1785 New Medical knowledge was based on noncomparative research, though Dictionary, placebo is described as 'a commonplace method there are some exceptions10O or medicine'2. In 1811, the revised Quincy's Lexicon-Medicum In 1801, John Haygarth reported the results of what defines placebo as 'an epithet given to any medicine adapted may have been the first placebo-controlled trial11. A more to please than to benefit the patient'3. common remedy for many diseases at that time was to apply metallic rods, known as Perkins tractors, to the body. These rods were supposed to relieve symptoms through the Department of Clinical Epidemiology and Biostatistics, Academic Medical electromagnetic influence of the metal. Haygarth treated Centre-University of Amsterdam, 1100 DE Amsterdam, The Netherlands; 'Center for Altemative Medicine Research, Beth Israel Deaconess Medical five patients with imitation tractors made of wood and Center, Harvard Medical School, Boston, MA 02215, USA; 2Centre for Reviews found that four gained relief. He used the metal tractors on and Dissemination, University of York, York YO1 5DD, UK the same five patients the following day and obtained Correspondence to: Dr Anton JM de Craen, Department of Clinical identical results: four of five subjects reported relief. It is Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands clear that Haygarth had the notion of a placebo effect when E-mail: [email protected] he stated that 'an important lesson in physic is here to be JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 92 October 1 999 learnt, the wonderful and powerful influence of the passions In 1938, the word placebo was first applied in reference of the mind upon the state and disorder of the body. This is to the treatment given to concurrent controls in a trial16. In too often overlooked in the cure of diseases'. He further previous years, uncontrolled observations had given wrote that the experiment 'clearly prove[d] what wonderful promising results with vaccines in preventing colds. effects the passions of hope and faith, excited by mere Controlled experiments, with persons in the control group imagination, can produce on disease'. In fact, Haygarth had receiving no treatment, had also given favourable results. not abandoned the Renaissance idea that imagination was The efficacy of cold vaccines was evaluated in several the major mediator between body and mind12. placebo-controlled trials. The authors reported that In 1863, Austin Flint tried to understand whether drugs given for articular rheumatism changed the natural history 'the students in the control groups were treated in of disease13. Flint placed 13 patients 'on the use of a exactly the same manner as those in the experimental placebo which consisted, in nearly all the cases, of the groups but received placebos instead of vaccine. The tincture of quassia, very largely diluted. This was given subjects in this group were given lactose-filled capsules regularly, and became well known ... as the placeboic remedy which were indistinguishable from the capsules contain- for rheumatism'. Flint, in accord with the understanding at ing the vaccine. They were prescribed with exactly the his time, had no idea of concurrent control, but concluded same instructions as the capsules containing the vaccine.' that 'the disease does end from self limitation' and that inert treatment worked. The explanation was fitted into The trial gave negative results, although the results in the prevailing dogma. Placebo was a fraud and deception that vaccine-treated groups were comparable with those in had the 'moral effect of a remedy given specially for the previously reported experiments. It was the substantial disease', but placebos did not affect the natural course of improvement in the placebo group that made the findings disease; they were a priori excluded from having such an negative. The conclusion reads impact. Placebos were therapeutic duds to manage patients, or, as in the Flint investigation, a camouflage behind which 'one of the most significant aspects of this study is the to watch nature take its course. great reduction in the number of colds which the mem- In the beginning of this century, the German physician bers of the control groups reported during the Adolf Bingel performed a large-scale comparative clinical experimental period. In fact these results were as good trial to assess the specific effect of diphtheria antitoxin as many of those reported in uncontrolled studies which serum in the treatment of diphtherial3. Bingel was con- recommended the use of cold vaccines'. cerned whether the antitoxin in the serum was responsible for the effect or whether treatment with serum not The placebo effect was born. containing the antitoxin would give comparable results. He alternately allocated 937 patients to either diphtheria antitoxin serum or normal horse serum (the placebo) and FROM 'HUMBLE HUMBUG' TO 'POWERFUL assessed the effect. He concluded that treatment with PLACEBO' normal horse serum achieved a similar clinical outcome to The view on placebos until the 1950s was that 'it cannot that with the antitoxic serum. harm and may comfort the patient'17. The placebo was In the 1930s, several important papers were published considered a 'humble humbug'18. While using placebos in with regard to the introduction of placebos in clinical research, clinicians began to recognize the therapeutic value research. Evans and Hoyle'4 and Gold and colleagues'5 of administering inert preparations to patients in control actually used the word placebo for the inert treatment groups of trials. Henry Beecher was one of the first given to controls in an experimental situation. Both papers researchers to note this phenomenon. In his 1955 landmark assessed the value of drugs used in the treatment of angina article 'The Powerful Placebo', he reviewed 15 placebo- pectoris in cross-over experiments and deceptively controlled trials and concluded that, on average, the administered placebos to the 'no-treatment' comparison magnitude of the placebo effect was 35.2%19. In retrospect, group. Various drugs were given, interspersed with periods it is difficult to understand the large impact this paper had of placebo administration. In both trials the drugs were since 13 of the 15 papers reviewed did not include no- judged to exert no specific action that might be useful in the treatment groups. They could therefore not distinguish treatment of angina. Gold and colleagues tried to explain between changes caused by the natural course of disease and why inert interventions might work: their points included those caused by placebo. Remarkably, in the two studies 'confidence aroused in a treatment', the 'encouragement that included no-treatment controls no differences were afforded by a new procedure' and 'a change of medical observed between the no-treatment group and the placebo 512 advisor'15.