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Placebo, a historical perspective
European Neuropsychopharmacology (2012) 22, 770–774
www.elsevier.com/locate/euroneuro
Placebo, a historical perspective Efrat Czerniaka, Michael Davidsona,b,n a
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel The Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel
b
Received 6 September 2011; received in revised form 22 March 2012; accepted 6 April 2012
1.
KEYWORDS
Abstract
Placebo; History; RCT
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. & 2012 Elsevier B.V. and ECNP. All rights reserved.
Introduction
The term placebo defines a therapy which is used for its non-specific psycho-physiological or presumed effect, but is without actual effect on the condition being treated. Placebo response is the difference between the non-specific beneficial response and that attributed to the natural history. Placebo effect is the (beneficial) effect which is derived from the context of the encounter – the rituals, the settings, and the clinician/healer-patient relationship – which is common to all treatments, as distinguished from
n
Corresponding author at: The Department of Psychiatry, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: +972 52 6668560. E-mail address: [email protected] (M. Davidson).
therapeutic benefits, produced by the specific or characteristic pharmacological or physiological effects of an active compound or intervention. The first mention of ‘‘placebo’’ is in St. Jerome’s mistranslation of the first word of the ninth line of Psalm 116. The Hebrew for ‘‘I will walk before the Lord’’, was translated by him into ‘‘Placebo Domino in regione vivorum’’ (‘‘I shall please the Lord in the land of the living’’) (Jacobs, 2000). Pleasing has a central meaning to the notion of placebo: placebo is associated with the pleasing of the patient by the therapist, of the therapist by the patient, or both. Since very few treatments with recognized and consistent beneficial effects have existed until the beginning of the 20th century, the history of medicine is the history of placebo. Effective placebo remedies have been ubiquitous in all societies and cultures, from the ancient Egypt (Shapiro
0924-977X/$ - see front matter & 2012 Elsevier B.V. and ECNP. All rights reserved. http://dx.doi.org/10.1016/j.euroneuro.2012.04.003
Placebo, a historical perspective and Shapiro, 1997) to today’s multi-billion-dollar alternative medicine (Singh and Ernst, 2008). From crocodile dung poultices, practiced by ancient Egyptians, to acupuncture, practiced today at the top medical centers all over the world, the placebo effect continues to be a trusted ally to the practicing clinician and an unavoidable hindrance to the clinical investigator.
2.
Ancient times (B.C.)
Dating back to 2100 B.C, In Babylonia and Assyria, we find that the modus operandus of the sorcerer (ashipu) and the physician (asu) was based on providing patients with empathy and comfort along with the ‘‘specific’’ remedy, thus taking full advantage of the placebo effect (Shapiro and Shapiro, 1997). The Egyptians were pioneers in writing medical texts, using medical terminology, exploring anatomy, and keeping records of procedures such as applying splints and bandages (Estes, 1989; Majno, 1975). One of the most valuable medical papyri, Ebers Papyrus, estimated to have been written around 1500 B.C., contained 842 prescriptions, though 700 were definitely medically worthless and the rest of questionable value (Estes, 1989; Kremers and Urdang, 1940). The ancient Egyptians were also the first to use the long-lasting technique of bloodletting in an attempt to purify the body (1000 B.C.) (Seigworth, 1980). The technique has survived for 2500 years, despite its ill effects. Same as in our time, techniques were constantly modified - from cutting to cupping to leaches - though the concepts behind them were seldom placed under scrutiny. Egyptian medicine had a great impact on the ancient Greeks, who added purges and dehydration to the medical toolbox. The history of Chinese medicine lists 4785 drugs, prescribed in four times as many (16,842) modes of prescriptions (Hume, 1940; Morse, 1934). Despite the fact that many of these drugs are used in current practice in China and the current popularity of Chinese medicine outside China, attempts to test these drugs’ effectiveness using modern trial methodologies have rarely proven them superior to placebo. Acupuncture, more than any other treatment, has gained the dedication of the Chinese and interest worldwide. Unfortunately, its vast popularity notwithstanding acupuncture still lacks biological plausibility and proper scientific evidence of effectiveness (Manheimer et al., 2005).
3.
The first eighteen centuries
Galen’s Pharmacopeia, with its 820 remedies, has dominated treatment for 1500 years and disappeared only in the 19th century, under pressure from the emerging scientific approach to medicine. Galen’s Pharmacopeia included any substance and mixture made of plants, bacteria, worms, reptiles, fish, human organs, tissue, bones powder, excretion, or extract in any phase, with or without the involvement of force majeure, magic, witchcraft, or any other intentional or unintentional action. Faulty deductive logic provided invaluable support to Galen’s placebo effect. ‘‘All who drink of this remedy recover in a short time except those whom it does not help, who all die. Therefore, it is obvious that it fails only in incurable cases.’’ Galen (30–200 AD).
771 During the 16th century Mithridatum, medicine’s universal remedy, later known as Theriac, was one of the oldest and most expensive drugs. It was concocted from dozens of substances and took six months to prepare (Majno, 1975). The legend tells that it was developed in the ancient Hellenistic kingdom of Anatolia (today’s Turkey) by the king Mithridates VI of Pontus, who was concerned about being poisoned. It is not clear whether he was trying to develop a universal medicine or an antidote for poison. When the Romans defeated him, his medical notes fell into their hands. Andromachus, Emperor Nero’s physician, added viper’s flesh to the mix as a main ingredient (Hodgson, 2001), and opium was often stirred in for good measure. In the 16th century Mattioli, an Italian physician, concocted an antidote for poison and for the plague from 230 ingredients, including opium and theriac Andromachus. Bezoar stones, believed to be the crystallized tears of a snake-bitten deer, turned out to be gallstones in the stomach of the deer. Bezoars spread from the Arab world of medicine to Europe and were used as a universal antidote. Emerging from Chinese, Indian, and Western literature, the mythological unicorn, with its spiraled horn, has become a symbol of purity and grace. It was believed to have the power to heal and to render poisoned water safe. Ground unicorn horn was among the most expensive placebo substances in the history of medicine and an important ingredient in 16th century medicine (Shepard, 1930). In fact, the substance was the left upper incisor tooth, spiraled indeed, of a narwhal whale. The absurdly high trading value gave rise to frauds and fakes, and records exist of individuals being tried and punished for such offenses. Again, faulty deductive logic proved an ally to placebo. Antonio Durazzini, active in Tuscany in 1622 during a most deadly epidemic, reported to his superiors in Florence that the poor peasants seem to be more robust and immune to disease than the rich. He based his observation on the fact that during epidemics the poor, who could not afford his bloodletting treatments, were less likely to die from the ravages of the epidemic than the rich, who could afford it. Despite faulty deduction, the limits of the medical sciences and the power of placebo were well understood, as evidenced by the words of Ambroise Pare (1510–1590): the physician’s duty is to ‘‘cure occasionally, relieve often, console always’’ (Gue rir quelquefois, soulager souvent, consoler toujours). God’s touch, already mentioned indirectly in the bible, was said to heal blindness, leprosy, and insanity. In ancient and medieval times, it evolved into belief in the ‘‘royal touch’’. It was practiced in Greece and Rome, and later by the English, French, and Spanish monarchies. In his 25-year reign in the 17th century, King Charles II has touched almost 100,000 individuals, some of whom no doubt achieved instant and long-lasting health. Richard Wiseman, the king’s doctor, who bore witness to the many hundreds of cures performed by the king’s touch (Bloch, 1973), remarked that in that period of English history more people have died of scrofula than ever before (Haggard, 1929). The belief in the royal touch faded in the 18th century, in parallel with social unrest and skepticism of the ideas of supernatural personae and of absolute monarchy. Eventually the skepticism spread to all areas of life, dismantling the entire social order (Bloch, 1973).
772 The French revolution and the Napoleonic realignment of Europe marked also the beginning of patient’s empowerment (Shapiro, 1960). Religious expiation, which used the removal of guilt, evil thoughts, and undesirable compulsions (Levin, 2009), lost some of its vigor but was far from defeated (Harrington, 1997). Along with somatic remedies, psychological healing came into being; anything—from primitive supernatural icons, sorcery, fetishes, and amulets, to shamans, witch doctors, or priests exorcising demons— was plausible. Religious mysticism, Christian faith healing and exorcism, invoking redemption by the almighty, were all supported by the church and practiced by clerics. To assert the supremacy of and distinguish between real redemption practiced by church-empowered priests, the sick and the ‘‘possessed’’ were challenged with fake holy objects. If they responded with exorcistic behavior to these fake objects, the ‘‘possession’’ was concluded to be not genuine and the response a placebo response (Kaptchuk et al., 2009). In the 18th century, a committee appointed by the Royal Academy of Medicine in Paris was charged with investigating the effectiveness of mesmerism. Mesmerism or animal magnetism was promoted by Franz Anton Mesmer, a charismatic German physician. It was based on his observations of redemption from exorcism, and provided a scientific aura and elaboration to this religious ritual (Podmore, 1963). This committee, with Benjamin Franklin amongst its members, was the first panel of physicians and scientists to try to distinguish between specific effects and placebo effect (Kaptchuk, 1998); the committee reported that there is nothing in animal magnetism without imagination and that imagination will do anyhow without the magnetism (Podmore, 1963). Based on what may be considered the first placebo-controlled trial, the panel rejected Mesmer’s therapeutic claim. The word placebo appeared, for the first time outside of the religious context, in the medical lexicon in the middle of the 18th century. The famous Scottish doctor and lecturer, William Cullen, used it in the context of treating and pleasing patients whom he could not cure with what he believed then were the active, appropriate treatments (Kerr et al., 2008). Despite significant progress during the 18th and the beginning of the 19th centuries, the practice of bloodletting has not perished, as evidenced by the notorious case of George Washington, whose cold and tonsillitis were treated by three protocols of bleeding, which finally led to his demise (Cohen, 2005). In 1827, only few years before bloodletting was subjected to scientific scrutiny, France was still importing 33 million leeches to cover local demand (Sigerist, 1958).
4. The 19th century—a few steps closer to modern medicine Enter the 19th century and the medical dictionary. Robert Hooper in Quincy’s Lexicon-Medicum, defined placebo as ‘‘an epithet given to any medicine adapted more to please than benefit the patient’’ (Hooper, 1811). The century was marked by several scientific developments, beginning with the study of pathological anatomy and of physiology, and the birth of modern pharmacology (Modell, 1976).
E. Czerniak, M. Davidson Despite these scientific advances, in 1858, in a grotto near by Lourdes, France, a 14-year-old peasant girl named Bernadette Soubirous has claimed that the Virgin Mary was revealed to her, a claim supported by the Catholic Church, which in time validated 67 miracles of the thousands reported. Since the cult’s inception, millions of people have made the pilgrimage to Lourdes, hoping to find remedy to every real or imaginary ailment. Not surprisingly, the only long-lasting (one year) effect of the pilgrimage was in the area of anxiety and depression (Morris, 1982). As more and more miracles were being subjected to scientific scrutiny, the success rate of a visit to Lourdes turned out to be in the range of 1 in 3 million and dropping. At this rate of success it has never been clear whether the number of resurgences and/or unambiguous cures is matched by the number of fatal road accidents incurred by the pilgrims on their way to and from Lourdes (water from Lourdes, delivered at home for a fixed fee plus postage, in sealed bottles, could improve the ratio miracles cures/road accidents).
5. The 20th century—placebo and medicine as we know it Surgery on the battlefields of WWII provided the anesthesiologist Henry Beecher with the opportunity to observe that when the supply of morphine has run out, plain saline solution might be an effective substitute to control pain. He summarized his observations on the placebo effect in a series of articles published in the 50s and 60s, claiming that up to 40% of the therapeutic effect of any intervention is due to the placebo effect (Beecher, 1955, 1961; Lasagna et al., 1954). He further claimed that patients suffering from chest pain experienced more relief when treated by enthusiastic surgeons than by skeptical ones (Beecher, 1961). The first serious challenge to Beecher’s fascination with placebo had to wait for several decades until a study (Hrobjartsson et al., 1998) claimed that in placebo-controlled randomized trials (RCTs) much of the physiological effect attributed to placebo is accounted for by the natural history of the disease, faulty reporting by patients eager to please the investigator, and other biases related to the study design. Hence, the authors claimed, one needs to have a non-treatment comparison (natural history) group in addition to the active and the placebo groups in order to identify the true physiological effects of placebo (Hr´ objartsson and Gøtzsche, 2010; Hr´ objartsson et al., 2011). Additionally, recent studies suggest that the response rate to either active or inactive intervention relies on higher odds of receiving the active intervention and on lower odds of receiving the inactive one (Rutherford et al., 2009; Sinyor et al., 2010). The advent in the late 40s and early 50s of treatments which, on the one hand, appeared to be very effective in treating life threatening diseases (antibiotics), but on the other hand had serious adverse effects, made the distinction between placebo and putative active drug effect more relevant and urgent, and led to the advent of the doubleblind RCTs (Greiner et al., 1950; Shorter, 2011). The quest of the scientific community and of the public at large to distinguish between the specific effect of a pharmacological or other intervention and the non-specific placebo effect
Placebo, a historical perspective took a number of paths. Already in the 70s, national regulatory agencies such as the FDA requested RCTs in order to approve the marketing of a drug. In the 80s, most funding agencies, such as the NIH, strongly advised researchers to employ placebo, and medical journals showed little enthusiasm to publish trials which did not include a placebo group. For the last three decades, the Cochrane foundation has been persistently demonstrating how precarious findings reporting positive results can be when they are not controlled for the placebo effect. Furthermore, government agencies continue to monitor the drugs effectiveness and adverse effects even after the drug has been approved for marketing and used by millions of individuals. Often treatments which appear effective today, may be doomed the day after. Even harmful methods such as bloodletting, occasionally generated a beneficial placebo response, accounting for the method’s endurance (Ernst, 2008).
6.
Placebo-good or bad? real or fake?
Since the 14th century, placebo has been associated with fakery, as demonstrated in the Latin prayers for the dead. Singers of placebo are paid mourners, or mourners falsely claiming a relation to the deceased in the hope of getting a share of the funeral meal (Aronson, 1999). In the Canterbury Tales, the sycophantic servant is called Placebo (Shapiro, 1968). It was Voltaire who pointed out how physicians employing the placebo effect took credit for the healings, which were the outcome of the natural history of the disease: ‘‘The art of medicine consists of amusing the patient while nature cures the disease’’. In this regard, Sir William Osler is quoted as saying: ‘‘one should treat as many patients as soon as possible with the new drug, while it still has power to heal’’. Still present in all religions and on a large scale, desired longevity and good health are being prayed for (Levin, 2009). The psychologist Sonja Lyubomirsky concluded that religiously-living people earn better health than the average population. According to her book (Lyubomirsky, 2008), the chances of an enthusiastic believer to survive the first six months after heart surgery are three times better than those of an atheist. Furthemore, head-and-neck cancer patients who were characterized as religious believers, have reported to be improving more than nonbelievers on a quality-of-life questionnaire (Becker et al., 2006). However, several controlled trials failed to demonstrate the efficacy of praying (Narayanasamy and Narayanasamy, 2008). At the same time, neuroscientists Persinger and Koren (developers of the God Helmet) claim to be able to induce a religious state by stimulating a subject’s temporal lobe using a weak magnetic field (Persinger et al., 2010), providing us with a provocative explanation of the link between religion and placebo. The moral dilemma of the use of placebo in clinical practice, the ‘‘benevolent deception,’’ continues to preoccupy clinicians, ethicists and the public at large (see also elsewhere in this issue). How can one be opposed to the healer’s emphatic reassurance, be it verbal, gestural, or accompanied by action (giving a pill, performing a procedure)? Yet Richard Cabot, in 1903, said that he was ‘brought up’ to use placebo supposedly like every other physician
773 (Cabot, 1978; de Craen et al., 1999), but he ultimately concluded, ‘‘I have not yet found any case in which a lie does not do more harm than good’’ (Newman, 2008). Most medical associations forbid the deliberate use of placebo but allow the use of interventions without biological plausibility or proof of efficacy based on RCTs. Anthropologists and medical sociologists argued that the placebo phenomenon was based greatly on worldwide ancient healing rituals involving symbols and metaphors of illness and recovery. Since humans have different paths to illness and recovery, placebos can work differently among individuals, cultures (Hahn and Kleinman, 1983; Moerman, 1983) and geographical regions (Chaudhry et al., 2008). The exploration of primitive societies and early medical records in prehistory can only lead to the assumption that placebo has been the dominant treatment in preliterate cultures. The earliest evidence, dating back more than seven thousand years, is possibly found in the remains of skulls which show marks of a rather sophisticated surgical procedure, demonstrating perhaps special care for the sick among early hominids (Australopithecus or Homo habilis) (Benedetti, 2009). This might mean that health management has evolved socially, and that the acts of care-giving and curing instilled trust and hope, improving quality of life within the group. The trusted group members who could perform these acts of healing became the shamans in early cultures and the doctors in modern societies (Humphrey, 2002). The social psychologist W.J. McGuire explains that there are ‘‘three stages in the life of an artifact.’’ First it is ignored; then it is controlled for its presumed contaminating effects; and finally, it is studied as an important phenomenon in its own right. Today, placebo is still mainly used as a comparison factor rather than being studied, although it has drawn more curiosity in the last few years (Harrington, 1997; Benedetti, 2009). Placebo and the placebo effect constitute a convergence point for the social, psychological, and physiological aspects of illness and health. Big, red, expensive pills are more effective than small, colorless, cheap pills, and dramatic procedures are more effective than plain pills. Skeptical scientists, atheists, agnostics, and religious believers are helped by their respective beliefs. The study of endorphins in the late 70s and imaging techniques in the late 90s and early 2000s, have added respectability to placebo. The notion that dopamine receptor binding in Parkinson’s disease can be affected by treatment with placebo (de la Fuente-Fernandez et al., 2001) underlines the idea that placebo is real and true. As always, science will have to uncover this truth through a process of trial and error.
Role of the funding source The Joseph Sagol Neuroscience Center at Sheba Medical Center Israel.
Contributors None.
774
Conflict of interest Authors report no financial interests or conflicts of interests in this research.
Acknowledgment Safra Nimrod for the language editing.
References Aronson, J., 1999. Please, please me. Br. Med. J. 318 (7185), 716. Becker, G., Momm, F., Xander, C., Bartelt, S., Zander-Heinz, A., Budischewski, K., et al., 2006. Religious belief as a coping strategy: an explorative trial in patients irradiated for headand-neck cancer. Strahlenther. Onkol. 182 (5), 270–276. Beecher, H.K., 1955. The powerful placebo. J. Am. Med. Assoc. 159 (17), 1602–1606. Beecher, H.K., 1961. Surgery as placebo. A quantitative study of bias. J. Am. Med. Assoc. 176, 1102–1107. Benedetti, F., 2009. Placebo effects: understanding the mechanisms in health and disease. Oxford University Press, New York. Bloch, M., 1973. The royal touch. Routeledge and Kegan Paul, London. Cabot, R.C., 1978. The use of truth and falsehood in medicine. Conn. Med. 42 (3), 189–194. Chaudhry, I., Neelam, K., Duddu, V., Husain, N., 2008. Ethnicity and psychopharmacology. J. Psychopharmacol. 22 (6), 673–680. Cohen, B., 2005. The death of George Washington (1732–99) and the history of cynanche. J. Med. Biogr. 13 (4), 225–231. de Craen, A.J., Kaptchuk, T.J., Tijssen, J.G., Kleijnen, J., 1999. Placebos and placebo effects in medicine: historical overview. J. R. Soc. Med. 92 (10), 511–515. de la Fuente-Fernandez, R., Ruth, T.J., Sossi, V., Schulzer, M., Calne, D.B., Stoessl, A.J., 2001. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science 293 (5532), 1164–1166. Ernst, E., 2008. A historical perspective on placebo. Clin. Med. 8 (1), 9–10. Estes, J.W., 1989. The medical skills of ancient Egypt. Science History Publications, Canton, MA. Greiner, T., Gold, H., Cattell, M., Travell, J., Bakst, H., Rinzler, S.H., et al., 1950. A method for the evaluation of the effects of drugs on cardiac pain in patients with angina of effort; a study of khellin (visammin). Am. J. Med. 9 (2), 143–155. Haggard, H., 1929. Devils, drugs and doctors. Harper and Brothers, New York. Hahn, R.A., Kleinman, A., 1983. Belief as pathogen, belief as medicine: ‘‘voodoo death’’ and the ‘‘placebo phenomenon’’ in anthropological perspective. Med. Anthropol. Q. 14 (4), 16–19. Harrington, A. (Ed.), 1997. The placebo effect: an interdisciplinary exploration. Harvard University Press, Cambridge. Hodgson, B., 2001. In the Arms of Morpheus: The Tragic History of Morphine, Laudanum and Patent Medicines. Firefly Books, Buffalo. Hooper, R., 1811. Quincy’s Lexicon-Medicum: A New Medical Dictionary. London. Hr´ objartsson, A., Gøtzsche, P.C., 2010. Placebo interventions for all clinical conditions (review). Cochrane Database Syst. Rev. 1. Hrobjartsson, A., Gotzsche, P.C., Gluud, C., 1998. The controlled clinical trial turns 100 years: Fibiger’s trial of serum treatment of diphtheria. Br. Med. J. 317 (7167), 1243–1245. Hr´ objartsson, A., Kaptchuk, T.J. and Miller, F.G., 2011. Placebo effect studies are susceptible to response bias and to other types of biases. J. Clin. Epidemiol. Hume, E.H., 1940. The Chinese way in medicine. John Hopkins Press, Baltimore. Humphrey, N., 2002. Great expectations: the evolutionary psychology of faith-healing and the placebo effect. In: von Hofsten, C.,
E. Czerniak, M. Davidson Backman, L. (Eds.), Psychology at the Turn of the Millennium, Vol. 2. Social Developmental, and Clinical Perspecties. Psychology Press, Hove, pp. 225–246. Jacobs, B., 2000. Biblical origins of placebo. J. R. Soc. Med. 93 (4), 213–214. Kaptchuk, T.J., 1998. Intentional ignorance: a history of blind assessment and placebo controls in medicine. Bull. Hist. Med. 72 (3), 389–433. Kaptchuk, T.J., Kerr, C.E., Zanger, A., 2009. Placebo controls, exorcisms, and the devil. Lancet 374 (9697), 1234–1235. Kerr, C.E., Milne, I., Kaptchuk, T.J., 2008. William Cullen and a missing mind-body link in the early history of placebos. J. R. Soc. Med. 101 (2), 89–92. Kremers, E., Urdang, G., 1940. The History of Pharmacy. J.B. Lippincott, Philadelphia. Lasagna, L., Mosteller, F., Von Felsinger, J.M., Beecher, H.K., 1954. A study of the placebo response. Am. J. Med. 16 (6), 770–779. Levin, J., 2009. How faith heals: a theoretical model. Explore (NY) 5 (2), 77–96. Lyubomirsky, S., 2008. The how of happiness: a scientific approach to getting the life you want. Penguin Press, US, New York. Majno, G., 1975. The healing hand. Harvard University Press, Cambridge. Manheimer, E., White, A., Berman, B., Forys, K., Ernst, E., 2005. Meta-analysis: acupuncture for low back pain. Ann. Intern. Med. 142 (8), 651–663. Modell, W., 1976. Origins and development of pharmacology. In: Modell, W., Schild, H.O., Wilson, H.O. (Eds.), Applied Pharmacology. W.B. Saunders, Philadelphia, pp. 7–28. Moerman, D., 1983. General medical effectiveness and human biology: placebo effects in the treatment of ulcer disease. Med. Anthropol. Q. 14 (3), 13–16. Morris, P.A., 1982. The effect of pilgrimage on anxiety, depression and religious attitude. Psychol. Med. 12 (2), 291–294. Morse, W., 1934. Chinese Medicine ‘‘Clio Medica: a series of primers on the history of medicine’’. P.B. Hoeber, New York. Narayanasamy, A., Narayanasamy, M., 2008. The healing power of prayer and its implications for nursing. Br. J. Nurs. 17 (6), 394–398. Newman, D.H., 2008. Hippocrates’ shadow. Scribner. Persinger, M.A., Saroka, K.S., Koren, S.A., St-Pierre, L.S., 2010. The electromagnetic induction of mystical and altered states within the laboratory. J. Conscious. Explor. Res. 1 (7), 808–830. Podmore, F., 1963. From Mesmer to Christian science. University Books, New Hyde Park. Rutherford, B.R., Sneed, J.R., Roose, S.P., 2009. Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychother. Psychosom. 78 (3), 172–181. Seigworth, G.R., 1980. Bloodletting over the centuries. N. Y. State J. Med. 80 (13), 2022–2028. Shapiro, A.K., 1960. A contribution to a history of the placebo effect. Behav. Sci. 5, 109–135. Shapiro, A.K., 1968. Semantics of the placebo. Psychiatr. Q. 42 (4), 653–695. Shapiro, A.K., Shapiro, E., 1997. The powerful placebo: from ancient priest to modern physician. Johns Hopkins University Press, Baltimore. Shepard, O., 1930. The lore of the unicorn. Houghton Mifflin, Boston. Shorter, E., 2011. A brief history of placebos and clinical trials in psychiatry. Can. J. Psychiatry 56 (4), 193–197. Sigerist, H.E., 1958. The great doctors. Doubleday, New York. Singh, S., Ernst, E., 2008. Trick or treatment: the undeniable facts about alternative medicine. W.W. Norton and Co.. Sinyor, M., Levitt, A.J., Cheung, A.H., Schaffer, A., Kiss, A., Dowlati, Y., et al., 2010. Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses. J. Clin. Psychiatry 71 (3), 270–279.
www.elsevier.com/locate/euroneuro
Placebo, a historical perspective Efrat Czerniaka, Michael Davidsona,b,n a
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel The Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel
b
Received 6 September 2011; received in revised form 22 March 2012; accepted 6 April 2012
1.
KEYWORDS
Abstract
Placebo; History; RCT
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. & 2012 Elsevier B.V. and ECNP. All rights reserved.
Introduction
The term placebo defines a therapy which is used for its non-specific psycho-physiological or presumed effect, but is without actual effect on the condition being treated. Placebo response is the difference between the non-specific beneficial response and that attributed to the natural history. Placebo effect is the (beneficial) effect which is derived from the context of the encounter – the rituals, the settings, and the clinician/healer-patient relationship – which is common to all treatments, as distinguished from
n
Corresponding author at: The Department of Psychiatry, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: +972 52 6668560. E-mail address: [email protected] (M. Davidson).
therapeutic benefits, produced by the specific or characteristic pharmacological or physiological effects of an active compound or intervention. The first mention of ‘‘placebo’’ is in St. Jerome’s mistranslation of the first word of the ninth line of Psalm 116. The Hebrew for ‘‘I will walk before the Lord’’, was translated by him into ‘‘Placebo Domino in regione vivorum’’ (‘‘I shall please the Lord in the land of the living’’) (Jacobs, 2000). Pleasing has a central meaning to the notion of placebo: placebo is associated with the pleasing of the patient by the therapist, of the therapist by the patient, or both. Since very few treatments with recognized and consistent beneficial effects have existed until the beginning of the 20th century, the history of medicine is the history of placebo. Effective placebo remedies have been ubiquitous in all societies and cultures, from the ancient Egypt (Shapiro
0924-977X/$ - see front matter & 2012 Elsevier B.V. and ECNP. All rights reserved. http://dx.doi.org/10.1016/j.euroneuro.2012.04.003
Placebo, a historical perspective and Shapiro, 1997) to today’s multi-billion-dollar alternative medicine (Singh and Ernst, 2008). From crocodile dung poultices, practiced by ancient Egyptians, to acupuncture, practiced today at the top medical centers all over the world, the placebo effect continues to be a trusted ally to the practicing clinician and an unavoidable hindrance to the clinical investigator.
2.
Ancient times (B.C.)
Dating back to 2100 B.C, In Babylonia and Assyria, we find that the modus operandus of the sorcerer (ashipu) and the physician (asu) was based on providing patients with empathy and comfort along with the ‘‘specific’’ remedy, thus taking full advantage of the placebo effect (Shapiro and Shapiro, 1997). The Egyptians were pioneers in writing medical texts, using medical terminology, exploring anatomy, and keeping records of procedures such as applying splints and bandages (Estes, 1989; Majno, 1975). One of the most valuable medical papyri, Ebers Papyrus, estimated to have been written around 1500 B.C., contained 842 prescriptions, though 700 were definitely medically worthless and the rest of questionable value (Estes, 1989; Kremers and Urdang, 1940). The ancient Egyptians were also the first to use the long-lasting technique of bloodletting in an attempt to purify the body (1000 B.C.) (Seigworth, 1980). The technique has survived for 2500 years, despite its ill effects. Same as in our time, techniques were constantly modified - from cutting to cupping to leaches - though the concepts behind them were seldom placed under scrutiny. Egyptian medicine had a great impact on the ancient Greeks, who added purges and dehydration to the medical toolbox. The history of Chinese medicine lists 4785 drugs, prescribed in four times as many (16,842) modes of prescriptions (Hume, 1940; Morse, 1934). Despite the fact that many of these drugs are used in current practice in China and the current popularity of Chinese medicine outside China, attempts to test these drugs’ effectiveness using modern trial methodologies have rarely proven them superior to placebo. Acupuncture, more than any other treatment, has gained the dedication of the Chinese and interest worldwide. Unfortunately, its vast popularity notwithstanding acupuncture still lacks biological plausibility and proper scientific evidence of effectiveness (Manheimer et al., 2005).
3.
The first eighteen centuries
Galen’s Pharmacopeia, with its 820 remedies, has dominated treatment for 1500 years and disappeared only in the 19th century, under pressure from the emerging scientific approach to medicine. Galen’s Pharmacopeia included any substance and mixture made of plants, bacteria, worms, reptiles, fish, human organs, tissue, bones powder, excretion, or extract in any phase, with or without the involvement of force majeure, magic, witchcraft, or any other intentional or unintentional action. Faulty deductive logic provided invaluable support to Galen’s placebo effect. ‘‘All who drink of this remedy recover in a short time except those whom it does not help, who all die. Therefore, it is obvious that it fails only in incurable cases.’’ Galen (30–200 AD).
771 During the 16th century Mithridatum, medicine’s universal remedy, later known as Theriac, was one of the oldest and most expensive drugs. It was concocted from dozens of substances and took six months to prepare (Majno, 1975). The legend tells that it was developed in the ancient Hellenistic kingdom of Anatolia (today’s Turkey) by the king Mithridates VI of Pontus, who was concerned about being poisoned. It is not clear whether he was trying to develop a universal medicine or an antidote for poison. When the Romans defeated him, his medical notes fell into their hands. Andromachus, Emperor Nero’s physician, added viper’s flesh to the mix as a main ingredient (Hodgson, 2001), and opium was often stirred in for good measure. In the 16th century Mattioli, an Italian physician, concocted an antidote for poison and for the plague from 230 ingredients, including opium and theriac Andromachus. Bezoar stones, believed to be the crystallized tears of a snake-bitten deer, turned out to be gallstones in the stomach of the deer. Bezoars spread from the Arab world of medicine to Europe and were used as a universal antidote. Emerging from Chinese, Indian, and Western literature, the mythological unicorn, with its spiraled horn, has become a symbol of purity and grace. It was believed to have the power to heal and to render poisoned water safe. Ground unicorn horn was among the most expensive placebo substances in the history of medicine and an important ingredient in 16th century medicine (Shepard, 1930). In fact, the substance was the left upper incisor tooth, spiraled indeed, of a narwhal whale. The absurdly high trading value gave rise to frauds and fakes, and records exist of individuals being tried and punished for such offenses. Again, faulty deductive logic proved an ally to placebo. Antonio Durazzini, active in Tuscany in 1622 during a most deadly epidemic, reported to his superiors in Florence that the poor peasants seem to be more robust and immune to disease than the rich. He based his observation on the fact that during epidemics the poor, who could not afford his bloodletting treatments, were less likely to die from the ravages of the epidemic than the rich, who could afford it. Despite faulty deduction, the limits of the medical sciences and the power of placebo were well understood, as evidenced by the words of Ambroise Pare (1510–1590): the physician’s duty is to ‘‘cure occasionally, relieve often, console always’’ (Gue rir quelquefois, soulager souvent, consoler toujours). God’s touch, already mentioned indirectly in the bible, was said to heal blindness, leprosy, and insanity. In ancient and medieval times, it evolved into belief in the ‘‘royal touch’’. It was practiced in Greece and Rome, and later by the English, French, and Spanish monarchies. In his 25-year reign in the 17th century, King Charles II has touched almost 100,000 individuals, some of whom no doubt achieved instant and long-lasting health. Richard Wiseman, the king’s doctor, who bore witness to the many hundreds of cures performed by the king’s touch (Bloch, 1973), remarked that in that period of English history more people have died of scrofula than ever before (Haggard, 1929). The belief in the royal touch faded in the 18th century, in parallel with social unrest and skepticism of the ideas of supernatural personae and of absolute monarchy. Eventually the skepticism spread to all areas of life, dismantling the entire social order (Bloch, 1973).
772 The French revolution and the Napoleonic realignment of Europe marked also the beginning of patient’s empowerment (Shapiro, 1960). Religious expiation, which used the removal of guilt, evil thoughts, and undesirable compulsions (Levin, 2009), lost some of its vigor but was far from defeated (Harrington, 1997). Along with somatic remedies, psychological healing came into being; anything—from primitive supernatural icons, sorcery, fetishes, and amulets, to shamans, witch doctors, or priests exorcising demons— was plausible. Religious mysticism, Christian faith healing and exorcism, invoking redemption by the almighty, were all supported by the church and practiced by clerics. To assert the supremacy of and distinguish between real redemption practiced by church-empowered priests, the sick and the ‘‘possessed’’ were challenged with fake holy objects. If they responded with exorcistic behavior to these fake objects, the ‘‘possession’’ was concluded to be not genuine and the response a placebo response (Kaptchuk et al., 2009). In the 18th century, a committee appointed by the Royal Academy of Medicine in Paris was charged with investigating the effectiveness of mesmerism. Mesmerism or animal magnetism was promoted by Franz Anton Mesmer, a charismatic German physician. It was based on his observations of redemption from exorcism, and provided a scientific aura and elaboration to this religious ritual (Podmore, 1963). This committee, with Benjamin Franklin amongst its members, was the first panel of physicians and scientists to try to distinguish between specific effects and placebo effect (Kaptchuk, 1998); the committee reported that there is nothing in animal magnetism without imagination and that imagination will do anyhow without the magnetism (Podmore, 1963). Based on what may be considered the first placebo-controlled trial, the panel rejected Mesmer’s therapeutic claim. The word placebo appeared, for the first time outside of the religious context, in the medical lexicon in the middle of the 18th century. The famous Scottish doctor and lecturer, William Cullen, used it in the context of treating and pleasing patients whom he could not cure with what he believed then were the active, appropriate treatments (Kerr et al., 2008). Despite significant progress during the 18th and the beginning of the 19th centuries, the practice of bloodletting has not perished, as evidenced by the notorious case of George Washington, whose cold and tonsillitis were treated by three protocols of bleeding, which finally led to his demise (Cohen, 2005). In 1827, only few years before bloodletting was subjected to scientific scrutiny, France was still importing 33 million leeches to cover local demand (Sigerist, 1958).
4. The 19th century—a few steps closer to modern medicine Enter the 19th century and the medical dictionary. Robert Hooper in Quincy’s Lexicon-Medicum, defined placebo as ‘‘an epithet given to any medicine adapted more to please than benefit the patient’’ (Hooper, 1811). The century was marked by several scientific developments, beginning with the study of pathological anatomy and of physiology, and the birth of modern pharmacology (Modell, 1976).
E. Czerniak, M. Davidson Despite these scientific advances, in 1858, in a grotto near by Lourdes, France, a 14-year-old peasant girl named Bernadette Soubirous has claimed that the Virgin Mary was revealed to her, a claim supported by the Catholic Church, which in time validated 67 miracles of the thousands reported. Since the cult’s inception, millions of people have made the pilgrimage to Lourdes, hoping to find remedy to every real or imaginary ailment. Not surprisingly, the only long-lasting (one year) effect of the pilgrimage was in the area of anxiety and depression (Morris, 1982). As more and more miracles were being subjected to scientific scrutiny, the success rate of a visit to Lourdes turned out to be in the range of 1 in 3 million and dropping. At this rate of success it has never been clear whether the number of resurgences and/or unambiguous cures is matched by the number of fatal road accidents incurred by the pilgrims on their way to and from Lourdes (water from Lourdes, delivered at home for a fixed fee plus postage, in sealed bottles, could improve the ratio miracles cures/road accidents).
5. The 20th century—placebo and medicine as we know it Surgery on the battlefields of WWII provided the anesthesiologist Henry Beecher with the opportunity to observe that when the supply of morphine has run out, plain saline solution might be an effective substitute to control pain. He summarized his observations on the placebo effect in a series of articles published in the 50s and 60s, claiming that up to 40% of the therapeutic effect of any intervention is due to the placebo effect (Beecher, 1955, 1961; Lasagna et al., 1954). He further claimed that patients suffering from chest pain experienced more relief when treated by enthusiastic surgeons than by skeptical ones (Beecher, 1961). The first serious challenge to Beecher’s fascination with placebo had to wait for several decades until a study (Hrobjartsson et al., 1998) claimed that in placebo-controlled randomized trials (RCTs) much of the physiological effect attributed to placebo is accounted for by the natural history of the disease, faulty reporting by patients eager to please the investigator, and other biases related to the study design. Hence, the authors claimed, one needs to have a non-treatment comparison (natural history) group in addition to the active and the placebo groups in order to identify the true physiological effects of placebo (Hr´ objartsson and Gøtzsche, 2010; Hr´ objartsson et al., 2011). Additionally, recent studies suggest that the response rate to either active or inactive intervention relies on higher odds of receiving the active intervention and on lower odds of receiving the inactive one (Rutherford et al., 2009; Sinyor et al., 2010). The advent in the late 40s and early 50s of treatments which, on the one hand, appeared to be very effective in treating life threatening diseases (antibiotics), but on the other hand had serious adverse effects, made the distinction between placebo and putative active drug effect more relevant and urgent, and led to the advent of the doubleblind RCTs (Greiner et al., 1950; Shorter, 2011). The quest of the scientific community and of the public at large to distinguish between the specific effect of a pharmacological or other intervention and the non-specific placebo effect
Placebo, a historical perspective took a number of paths. Already in the 70s, national regulatory agencies such as the FDA requested RCTs in order to approve the marketing of a drug. In the 80s, most funding agencies, such as the NIH, strongly advised researchers to employ placebo, and medical journals showed little enthusiasm to publish trials which did not include a placebo group. For the last three decades, the Cochrane foundation has been persistently demonstrating how precarious findings reporting positive results can be when they are not controlled for the placebo effect. Furthermore, government agencies continue to monitor the drugs effectiveness and adverse effects even after the drug has been approved for marketing and used by millions of individuals. Often treatments which appear effective today, may be doomed the day after. Even harmful methods such as bloodletting, occasionally generated a beneficial placebo response, accounting for the method’s endurance (Ernst, 2008).
6.
Placebo-good or bad? real or fake?
Since the 14th century, placebo has been associated with fakery, as demonstrated in the Latin prayers for the dead. Singers of placebo are paid mourners, or mourners falsely claiming a relation to the deceased in the hope of getting a share of the funeral meal (Aronson, 1999). In the Canterbury Tales, the sycophantic servant is called Placebo (Shapiro, 1968). It was Voltaire who pointed out how physicians employing the placebo effect took credit for the healings, which were the outcome of the natural history of the disease: ‘‘The art of medicine consists of amusing the patient while nature cures the disease’’. In this regard, Sir William Osler is quoted as saying: ‘‘one should treat as many patients as soon as possible with the new drug, while it still has power to heal’’. Still present in all religions and on a large scale, desired longevity and good health are being prayed for (Levin, 2009). The psychologist Sonja Lyubomirsky concluded that religiously-living people earn better health than the average population. According to her book (Lyubomirsky, 2008), the chances of an enthusiastic believer to survive the first six months after heart surgery are three times better than those of an atheist. Furthemore, head-and-neck cancer patients who were characterized as religious believers, have reported to be improving more than nonbelievers on a quality-of-life questionnaire (Becker et al., 2006). However, several controlled trials failed to demonstrate the efficacy of praying (Narayanasamy and Narayanasamy, 2008). At the same time, neuroscientists Persinger and Koren (developers of the God Helmet) claim to be able to induce a religious state by stimulating a subject’s temporal lobe using a weak magnetic field (Persinger et al., 2010), providing us with a provocative explanation of the link between religion and placebo. The moral dilemma of the use of placebo in clinical practice, the ‘‘benevolent deception,’’ continues to preoccupy clinicians, ethicists and the public at large (see also elsewhere in this issue). How can one be opposed to the healer’s emphatic reassurance, be it verbal, gestural, or accompanied by action (giving a pill, performing a procedure)? Yet Richard Cabot, in 1903, said that he was ‘brought up’ to use placebo supposedly like every other physician
773 (Cabot, 1978; de Craen et al., 1999), but he ultimately concluded, ‘‘I have not yet found any case in which a lie does not do more harm than good’’ (Newman, 2008). Most medical associations forbid the deliberate use of placebo but allow the use of interventions without biological plausibility or proof of efficacy based on RCTs. Anthropologists and medical sociologists argued that the placebo phenomenon was based greatly on worldwide ancient healing rituals involving symbols and metaphors of illness and recovery. Since humans have different paths to illness and recovery, placebos can work differently among individuals, cultures (Hahn and Kleinman, 1983; Moerman, 1983) and geographical regions (Chaudhry et al., 2008). The exploration of primitive societies and early medical records in prehistory can only lead to the assumption that placebo has been the dominant treatment in preliterate cultures. The earliest evidence, dating back more than seven thousand years, is possibly found in the remains of skulls which show marks of a rather sophisticated surgical procedure, demonstrating perhaps special care for the sick among early hominids (Australopithecus or Homo habilis) (Benedetti, 2009). This might mean that health management has evolved socially, and that the acts of care-giving and curing instilled trust and hope, improving quality of life within the group. The trusted group members who could perform these acts of healing became the shamans in early cultures and the doctors in modern societies (Humphrey, 2002). The social psychologist W.J. McGuire explains that there are ‘‘three stages in the life of an artifact.’’ First it is ignored; then it is controlled for its presumed contaminating effects; and finally, it is studied as an important phenomenon in its own right. Today, placebo is still mainly used as a comparison factor rather than being studied, although it has drawn more curiosity in the last few years (Harrington, 1997; Benedetti, 2009). Placebo and the placebo effect constitute a convergence point for the social, psychological, and physiological aspects of illness and health. Big, red, expensive pills are more effective than small, colorless, cheap pills, and dramatic procedures are more effective than plain pills. Skeptical scientists, atheists, agnostics, and religious believers are helped by their respective beliefs. The study of endorphins in the late 70s and imaging techniques in the late 90s and early 2000s, have added respectability to placebo. The notion that dopamine receptor binding in Parkinson’s disease can be affected by treatment with placebo (de la Fuente-Fernandez et al., 2001) underlines the idea that placebo is real and true. As always, science will have to uncover this truth through a process of trial and error.
Role of the funding source The Joseph Sagol Neuroscience Center at Sheba Medical Center Israel.
Contributors None.
774
Conflict of interest Authors report no financial interests or conflicts of interests in this research.
Acknowledgment Safra Nimrod for the language editing.
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