BY: PAUL ENCK & SIBYLLE KLOSTERHALFEN | DECEMBER 6, 2018
In comparison to Henry Beecher’s much-cited paper, “The Powerful placebo,” of 1955 (1), Stewart Wolf’s paper, “The pharmacology of placebos,” of 1959 (2) is today almost forgotten; it came along less spectacularly but more scientifically solid, hiding its implicit provocation (there is a biology underlying the placebo effects) behind a seemingly serious title and in an even more serious journal, the reputable Pharmacological Reviews.
While Beecher assumed a specific personality of the placebo-reactor, Wolf’s assumption was that the underlying mechanism of placebos must have a pharmacology — a biology, in a broader sense. Pioneering psychosomatic medicine Stewart Wolf (1914 – 2005) was a physician and pioneer in psychosomatic medicine who trained at Yale and Johns Hopkins, interned at Cornell, and later became a professor of medicine at the University of Oklahoma. He pioneered studies on the role of the psyche and psychosocial conditions on cardiac activity and cardiovascular events. However, his main interest and long-time devotion was the gastrointestinal tract and digestive functions. He became famous and known for his work on Tom, a single patient with a gastric fistula, a summary presented at an annual meeting of the American Medical Association in 1947 (3), but published as a book (Wolf & Wolff: Human Gastric Function, Oxford University Press, 1943) some years before.
While working at Cornell University and the New York Hospital in NYC, and under the guidance of Harold George Wolff (1898-1962), a pioneer specialist in headache and migraine research, he explored human gastric functions in a fistulated patient who had burned his esophagus and received an artificial gastric opening (fistula) that allowed him to feed — much along the tradition of another famous individual with a gastric fistula that had been studied nearly one hundred years earlier by William Beaumont (1785-1853) and that Wolf described in a historical vignette in 1981 (4).
While initially laughed at because of its nature as a single case documentation that does not allow generalization, the study of Tom, their patient, allowed Wolf & Wolff many basic observations which became appreciated as milestones in stress research much later and confirmed earlier observations on the role of stress and emotions on gastrointestinal motility and secretion, as Walter Cannon (1871-1945) had explored in animals; other similar case reports followed (5).
They were, only a few years later, replicated experimentally in healthy individuals as well as in patients with irritable bowel syndrome (or irritable colon, as it was called in those days) with the help of novel technologies, such as manometric recording devices and tubes allowing measurements inside the gastrointestinal tract, such as by Thomas Almy (1915-2002) and colleagues (6).
Nausea and other intestinal conditionsBeecher (1), Wolf (2), and others had noted that placebo effects were specifically high in clinical conditions producing nausea symptoms, e.g. motion and seasickness, cancer chemotherapy, postoperative ileus, anorexia, panic disorder, and also pregnancy. Therefore, it is not surprising to see that Wolf’s interest in gastrointestinal symptoms and conditions coincided with this specific clinical focus. Nausea, and to some degree also vomiting (the motor response to increased nausea), resembles both peripheral (intestinal) as well as central components (7). This makes nausea symptoms susceptible to both central and peripheral stimuli, as is documented in clinical studies treating nausea symptoms which showed overall high placebo responses. As we have shown in various instances, nausea symptoms are easy to elicit via conditioning in females and via verbal suggestions in men.
The pharmacology of placebosWhen we (8) were invited by the journal Pharmacological Reviews to contribute a review article on placebo effects in 2014, we first screened this journal to identify papers that had already dealt with the placebo topic and found Stewart Wolf’s paper of 1959, which had been rarely cited in the scientific literature. In fact, Google Scholar — accessed November 18, 2018 — informs us that it had only been cited 272 times ever since, compared to 2312 citations of Beecher’s “The powerful placebo,” of 1955.
The title already must have been seen as a provocation, of which Wolf was well aware of. “The title presents a picturesque contradiction. Pharmacology concerns itself with the chemical properties of drugs and their effects on biological mechanisms. Placebos produce effects on biological mechanisms independent of their chemical properties” (2, p 689).
While the medical community still puzzled over “placebo reactors” (as Beecher called them) and searched for psychological explanations of the placebo effect and the personality characteristics of placebo-responders, Wolf argues that the underlying mechanisms — conditioning and expectancies — have a biology and pharmacology that he set of to explore.
Quite different from Henry Beecher, who semi-meta-analyzed 15 clinical placebo-controlled trials in different areas of medicine, Stewart Wolf’s narrative review is predominantly about experimental work of his contemporaries who explored the mechanisms behind the placebo effects as it can be elicited in the laboratory. For this, he identified some 30 papers that he discussed under various aspects: That placebos can induce increase as well as decrease of physiological responses (e.g. acid secretion), that it can produce toxic actions (nowadays called nocebo effects), their mechanisms of action (conditioning, expectancy, others), the role of unconsciousness, the use of placebos in therapeutic research, placebo effects in surgery, the therapeutic design to study the placebo effect (including the need for a no-treatment control), the question of placebo reactors — no consistency, no predictability — and the place of placebo (and its ethics) in clinical routine.
To illustrate, he cites a study by Gliedman (9) in which patients with bleeding ulcers receive a placebo either with instructions that this would be a powerful medicine that would improve symptoms, or that it was a novel experimental drug of unknown efficacy, resulting in 70 and 25% of symptom improvement in the two groups, respectively.
Are we really standing on the shoulders of giants?Given the small database of the accumulated knowledge on placebo effects/responses in the 1950s of the last century — in toto probably fewer than 100 papers altogether — specifically when compared to today’s >4000 papers including reviews, meta-analyses, RCT re-analyses, and experimental studies (10), it is surprising to see how much could have been gained from it and how little the addition of several thousand papers in the last 70 years has added to it. So are we dwarfs, standing on the shoulders of these giants (to again use this allegory that Robert Merton has explored: R.Merton, Standing on the shoulders of Giants, 1968), but do not see further, because we are just looking in the wrong direction — for instance, only in the direction the giants have pointed us to?
Clearly, Henry K. Beecher and Stewart Wolf were addressing a “hot topic” that, at their time, had received much attention through the introduction of placebo-controlled trials for testing of novel drugs, for which Wolf noted objections against, similar to Beecher. And he refers to a “Cornell Conferences on Therapy” series with one on the use of placebos in therapy organized in 1946 that may at their time have been more important than any of their two papers.
The question, therefore, is whether the development of placebo research as described (10) would have happened without these to seminal papers, or whether it would have taken an entirely different route. And what, if not these papers and their reception by the scientific community, may have driven the community into the direction taken. This will be discussed in a future posting.
This is part 12 of a series covering “placebo” provided by Paul Enck and Sibylle Klosterhalfen from the Tübingen University Hospital. Continuous updates on placebo research can be found at www.jips.online.
1) Beecher HK. The powerful placebo. Journal of the American Medical Association. 1955;159(17):1602-6.
2) Wolf S. The pharmacology of placebos. Pharmacological reviews. 1959;11:689-704.3) Wolf S, Wolff HG. Function of the stomach as observed in fistulous human subjects, with special reference to the action of drugs and the effects of vagotomy. The American journal of medicine. 1947;3(1):127.
4) Wolf S. The psyche and the stomach. A historical vignette. Gastroenterology. 1981;80(3):605-14.
5) Engel GL, Reichsman F, Segal HL. A study of an infant with a gastric fistula. I. Behavior and the rate of total hydrochloric acid secretion. Psychosomatic medicine. 1956;18(5):374-98.
6) Almy TP, Tulin M. Alterations in colonic function in man under stress; experimental production of changes simulating the irritable colon. Gastroenterology. 1947;8(5):616-26.7) Enck P, Klosterhalfen S. The brain is not empty: Central mechanisms of nausea and vomiting. Neurogastroenterology and motility. 2016;28(8):1278.
8) Schedlowski M, Enck P, Rief W, Bingel U. Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice. Pharmacological reviews. 2015;67(3):697-730.
9) Gliedman LH, Nash EH, Jr., Imber SD, Stone AR, Frank JD. Reduction of symptoms by pharmacologically inert substances and by short-term psychotherapy. AMA archives of neurology and psychiatry. 1958;79(3):345-51.
10) Enck P, Horing B, Broelz E, Weimer K. Knowledge Gaps in Placebo Research: With Special Reference to Neurobiology. International review of neurobiology. 2018;139:85-106.