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SECTION III REGULAR AND SPECIAL FEATURES: Orthopaedic • Radiology • Pathology Conference

The Origins of Modern Clinical Research

Green, Stuart A. MD

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Clinical Orthopaedics and Related Research: December 2002 - Volume 405 - Issue - p 311-319, 325
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Abstract

It has become popular among clinical investigators to distinguish between evidence-based treatment strategies and those that arise from habit, conjecture, or hypothetical considerations. Moreover, the most reliable of the evidenced-based determinations in clinical research are considered to be derived from single-blind or double-blind, placebo-controlled randomized clinical trials. The randomized clinical trial currently is considered the gold standard for evaluating the alleged value of newly developed pharmaceuticals, medical devices, and treatment protocols. It is difficult, if not impossible, to market an innovative drug or device in the modern world without first doing such an investigation.

The characteristic features of placebo-controlled clinical evaluations include two essential elements: a sham intervention and subject ignorance about the bogus nature of that intervention. Therefore, when looking into the origins of modern clinical research, one must find the earliest example of an inquiry that arrived at its conclusions about the claimed benefits of a therapeutic protocol by using intentional subject ignorance combined with real and sham intervention.

Considering the obvious importance of such blinded placebo-controlled investigations, the question naturally arises: Where did this method of evaluating the claimed benefit of a particular therapy arise? Credit for developing the modern clinical trial sometimes is given to Harry Gold, MD of New York’s Cornell School of Medicine. From the 1930s through the 1950s, working in conjunction with various colleagues, Gold conducted a series of investigations into the benefits of numerous pharmaceutical substances, including ether, theobromine, and aminophylline. 13,17,19 The terms blind test and double-blind test first appear in studies published in 1935 19 and 1950, 17 respectively.

Some scholarly reviews and monographs dealing with the origins of modern scientific methods of clinical research, 2,28 convey a commonly held, but erroneous, perception that the single-blind and double-blind placebo-controlled studies first appeared in reports from a group of clinical investigators in Michigan (1931) 1 or at London Hospital (1933). 7 In the Michigan tuberculosis treatment trial of 1926 to 1931, for example, 12 patients were treated with a sodium-gold-thiosulfate combination and 12 other patients (carefully matched for numerous characteristics) were administered the placebo–distilled water.

Kaptchuk, in a particularly erudite and well-documented review, 21 traced the history of blind assessment with sham intervention to a French royal commission inquiry into the mesmerism craze of the 1780s. He was unable to find any earlier references to that method of analyzing the value of controversial medical therapies.

King Louis XVI, to ascertain the validity of Dr. Franz Mesmer’s claims of miraculous cures by use of animal magnetism, appointed a commission of distinguished scientists and physicians to look into the matter. The inquiry was headed by Benjamin Franklin, the American ambassador to France and a celebrated scientist in his own right.

The strategy Franklin and the other commission members used to debunk Franz Mesmer’s assertions about illness and treatment appear in the first published report 12 of what now is called a single-blind placebo-controlled clinical trial. Subsequent evaluators, looking into the legitimacy of certain therapeutic devices and medications, explicitly duplicated the commission’s method of using intentional subject ignorance, combined with real and sham treatment, to arrive at their conclusions.

Before considering the royal commissions methods and conclusions, however, it would be worthwhile to briefly review the facts surrounding the phenomenon that literally mesmerized Parisians in prerevolution France. 3,23,29 Franz Anton Mesmer, a Swiss-born Viennese physician arrived in Paris in February 1778, having been forced out of Vienna by his medical colleagues. They considered Mesmer a charlatan and perhaps also were jealous of the phenomenal growth of his clinical practice. Mesmer believed that an ultrafine magnetic fluid, emanating from the stars and planets, passed through all objects in the universe, animate and inanimate. He attributed illness to a blockage of the magnetic fluid’s natural flow and thought that he had the power to unplug this barrier.

At first, Mesmer used magnets for the curative procedure, sometimes after the patient had swallowed iron filings, a concept he learned from a prelate named Father Hell. 4 Subsequently, however, Mesmer dispensed with magnets and used his hands or an iron rod to effect the remedy. In this way, Mesmer emphasized the difference between earlier treatments based on mineral magnetism, which entailed the use of magnets, and his version, animal magnetism, which did not.

The regimen started with pretreatment preparation that used soft lighting, eerie music, and other measures now recognized as helping to evoke a hypnotic state. Speaking softly, Mesmer generated an altered type of consciousness in the patient. Mesmer often is credited with being the father of clinical hypnotism, although the practice of promoting hypersuggestion can be traced back to ancient Egypt. 25

Part of Mesmer’s therapeutic program involved inducing a crisis whereby a patient either would faint or convulse uncontrollably (aspects of the treatment which tended to alarm observers). The patient then would be carried, if necessary, to a padded crisis room to avoid injury during the fits.

Having married a wealthy high-society widow, Mesmer’s popularity and fame grew rapidly during the early years of his practice in Vienna. One close friend was Leopold Mozart, whose prodigious children were the talk of the town. Mesmer commissioned young Wolfgang’s first produced opera (Bastien und Bastienne) and subsequently was mentioned by name in Cosi fan tutti. 4

At first, Mesmer had supporters in the Viennese medical profession, but after he claimed to have temporarily restored sight to the blind teen-aged pianist Maria Theresa Paradis, his detractors got the upper hand. The girl’s father alleged that Mesmer was interested in more than her visual difficulties and snatched his daughter from Mesmer’s home. (She had moved in during treatment.) 27 Thoroughly disgraced, and probably wrongfully accused, Mesmer left his wife in Vienna and headed for Paris, not returning until after her demise.

On arriving in Paris, Mesmer, fearing resistance from other physicians, tried to make a presentation to the learned medical society but was rebuffed. The public, however, quickly became enamored with Mesmer and his seemingly successful method of treatment, especially after some members of the royal family, Marie Antoinette included, signaled their approval.

Mesmer and some acquaintances set up a partnership to teach a limited number of practitioners magnetic therapy, eventually spreading the method throughout France. The Societies of Harmony, as the mesmerist groups were called, outlasted Mesmer’s own sojourn in France. 5 (Mesmer eventually would get into a bitter dispute with his partners over the profits generated by the teaching program.)

Dr. Charles d’Eslon, physician to Louis XVI’s brother, became one of Mesmer’s earliest disciples. Because Mesmer, who did not have a French medical license, had to move his clinic to the outskirts of town, d’Eslon had great success as a Parisian mesmerist, although he was hardly the only one. For 5 years, between 1779 and 1784, the French became obsessed with mesmerism; more pamphlets and newspaper articles were devoted to the subject than to balloon flight, another novelty of the era. 4

So many patients (and dilettantes) clamored for treatment that Mesmer and his disciples often used a baquet (bucket) for group therapy. The device, a large wooden tub approximately 10 feet in diameter and 1.5 feet deep, contained magnetized water and also may have held iron filings, broken bits of glass, or geometrically arranged bottles filled with water earlier magnetized by the treater. The baquet was covered by wooded planking through which bent iron rods protruded. The patients receiving therapy would sit around the tub and either grip a rod or touch it to the body part needing treatment (Fig 1). Sometimes two or three circles of patients would surround the baquet, interconnected by ropes or by having each patient grasp the thumb of the adjacent person between his or her own thumb and index finger. The mesmerist would walk around the circle, magnetize the water in the tub and touch the participants with his hand or an iron staff, thereby inducing convulsions, fainting spells, and other forms of crisis therapy. When such a session was held outdoors, a tree, properly magnetized by the mesmerist, was substituted for the baquet (Fig 2).

Fig 1.
Fig 1.:
The patients are sitting around a baquet during treatment. One man with a crutch touches his foot to the baquet. Mesmer, on the right, attends a woman who is in crisis, having fainted. From a contemporary 18th century etching.
Fig 2.
Fig 2.:
D’Eslon is shown magnetizing a tree, with patients in crisis at the base.

Considering the dangers of traditional eighteenth century medical treatment (with its purgatives, emetics, and bloodletting), it is no surprise that the alternative offered by Mesmer and his disciples was so popular. Moreover, Mesmer, being a medical doctor, may have had a knack for recognizing, and excluding from his clinic, serious and incurable organic maladies and handling mostly psychosomatic ailments.

In 1784, Louis XVI, bowing to pressure from the medical establishment to investigate mesmerism, created the Royal Commission of Inquiry, consisting of physicians and distinguished scientists. Among the commissioners were Benjamin Franklin, the oldest member, selected, no doubt, for his expertise in electric phenomena; Antoine Lavoisier, the father of modern chemistry; Jean Sylvain Bailly, a distinguished royal astronomer and later president of the National Assembly and mayor of Paris after the revolution; and Joseph-Ignace Guillotin, a well-known physician who argued successfully for humane executions with the device that later took his name. The other members of Franklin’s commission included his friend, the chemist and electrician Jean-Baptiste Le Roy; the geographer Gabriel de Bory; and physicians Jean Francois Borie, Charles Louis Sallin (a physiologist and pathologist), and Jean d’Arcet. 6

Almost immediately after the formation of the commission, the king appointed several members of the newly formed Royal Society of Medicine to a second commission for a parallel investigation into mesmerism. A third, unofficial investigation also took place. 6

Mesmer objected to the commission’s proposed plan of studying animal magnetism, so the royal commissioners chose to scrutinize instead d’Eslon’s mesmerist activities, causing a major rift between master and pupil.

Although all three groups prepared reports, it is the product of the Franklin commission that has become the most famous. Gould 14 called this report “. . . a key document in the history of human reason,” primarily because of the methods the commissioners used to probe Mesmer’s claims. Gould said the report “. . . should be rescued from its current obscurity, translated into all languages, and reprinted by organizations dedicated to the unmasking of quackery and the defense of rational thought.”14

From the outset, the commissioners chose to avoid looking into the mesmerists’ alleged cures. Instead, they focused on the validity of animal magnetism per se for, as the commission’s report to the king stated, “Animal magnetism may exist without being useful, but it cannot be useful if it does not exist.”9

It seems that Lavoisier had a preconceived notion about how to conduct the investigation, as his personal writings set out the fundamental principles of the assessment. Lavoisier probably should get the credit for devising the basic research design because, in a preliminary analysis of animal magnetism, he suggested magnetizing subjects without their knowledge and making a person think they were magnetized when they were not. 6 However, planning meetings were scheduled at Franklin’s home to discuss the inquiry, so the venerable philosopher’s input was involved at some stage of the planning.

Benjamin Franklin had earlier given some thought to the mesmerism phenomenon. Franklin, who had once met Mesmer, 24 was asked by a correspondent about his opinion on mesmerism. Although he deferred judgment about the specifics of Mesmer’s claims, Franklin wrote, “There being so many disorders which cure themselves and such a disposition in mankind to deceive themselves and one another on these occasions . . . That delusion may however in some cases be of use while it lasts . . . If these people can be persuaded to forbear their drugs in expectation of being cured . . . they may possibly find good effects tho’ they mistake the cause.”10

The commissioners did their investigations at several locations, including d’Eslon’s clinic, Lavoisier’s home, and Franklin’s Passy gardens. Franklin suffered from gout and kidney stones so he attended only the session conducted at his own residence. Benjamin Franklin Bache (Benny), then 14 years old, witnessed the experiments done in his grandfather’s gardens. Benny 23,24 and the Commission’s report describe how a previously treated boy was blindfolded (truly a blind assessment) and led to trees he was told had been magnetized by the mesmerist, although some were not. The lad responded to a placebo tree as though it were magnetized: he fainted and convulsed. Similar inappropriate responses were observed at other test locations when the subjects were give a glass of water that was or was not magnetized. Likewise, the blindfolded patients of d’Eslon convulsed when magnetized by fake mesmerists, whereas skeptical subjects (the commission members) could not be induced to a response, even by d’Eslon himself.

D’Elson, after witnessing the outcome of the experiments, was persuaded by what he saw. According to the commission’s report, d’Eslon “declared in our session held at the house of Dr. Franklin the 19th of June [1784] that he thought he might lay it down as a fact that the imagination had the greatest share of the effects of animal magnetism . . .”12 The fact that d’Eslon’s concession occurred in Franklin’s residence is no coincidence. Franklin, according to Thomas Jefferson, was not prone to speak out much in public, but when he finally did have something to say, it was to “the main point which was to decide the question.”20

The royal commission’s report castigated mesmerism. The commissioners concluded that there was no such thing as animal magnetism, attributing the effects of mesmerism to the subjects’ imagination. 9 (By not evaluating the clinical outcomes, however, the commissioners missed an opportunity to confirm or refute the effectiveness of such imagination in curing certain illnesses.)

Although the commissioners’ names did not appear on the cover of the official report, Franklin’s signature was first at the end. 12 Therefore, regardless of his contribution to the project, Franklin was first author and senior author and therefore is rightly credited by posterity for the report’s ensuing influence.

Thousands of copies of the report were printed, and Franklin was viewed by many as Mesmer’s main antagonist. The first English translation of the document is entitled, Report of Dr. Benjamin Franklin and other commissioners . . . 9 Because there were so many coauthors, a citation of the report in a modern journal (Science) would read: B. Franklin et al. . .

A secret Franklin commission report also was presented to the king. It dealt with those aspects of mesmerism that the commissioners considered salacious, such as the manner in which the mesmerists stroked the lower abdomen and thighs of the female patients while magnetizing them. 11 Fifteen years after this second report was submitted, a public version appeared. By then, the mesmerism fad had passed, and the French were preoccupied with more important matters, so the printed version of this report received little notice.

What is so ironic about the royal inquiry’s conclusion is that Mesmer was, to some extent at least, correct about the existence of animal magnetism. It now has been shown conclusively that certain migrating animals locate their breeding grounds by being sensitive to subtle variations in the earth’s magnetic field. To do so, they must possess an organ (or region of the brain) that responds to differences in natural magnetic intensity. 22,26

Despite history casting doubt on some of their conclusions, the commissioners clearly showed that a mesmerist was not accomplishing anything physical while attempting to channel the magnetic forces of the universe through the bodies of his patients.

The Franklin commission’s report, and those of the other inquiries, were widely disseminated. In response, pamphlets criticizing or supporting the investigation appeared. At least two stage plays ridiculed mesmerism. A political cartoon of the period showed a donkey-eared Mesmer, pockets stuffed with cash, flying off on a broomstick as Franklin holds the commission’s report aloft (Fig 3). Some mesmerists charged that the commissioners had unfairly condemned the greatest advance in healthcare ever discovered. They attributed the commissioners’ motives to academic and professional despotism. These radical mesmerists produced a series of pamphlets that first appeared as attacks on the contents of royal commission reports but gradually became vociferous assaults on the monarchy. The increasing popularity of the radical mesmerists’ perspective contributed, in some ways, to the antiroyalist sentiment leading to the French Revolution. 5

Fig 3.
Fig 3.:
Mesmer, shown with donkey ears and holding a bag of money in his right hand, flies off on a broomstick, accompanied by d’Eslon as Benjamin Franklin and the other royal commissioners enter on the left, holding up the report that debunked mesmerism.

Mesmer eventually left Paris, toured other French and European cities where he still was popular, and finally settled close to his birthplace in Switzerland. Near the end of his days, Mesmer still continued to defend his concepts about animal magnetism and even drifted into occult practices. He became convinced that animal magnetism, properly applied, permitted clairvoyance and precognition, among other things. He claimed to have magnetized the sun. 3

The practice of therapeutic mesmerism continued to evolve after Mesmer left Paris. Puységur, a disciple of Mesmer, recognized that the convulsive crisis was not necessary for clinical success. Later, the Englishman James Braid realizing that the mesmerized subject was in a hypersuggestable state, coined the term hypnosis for the process. To this day, clinical hypnotism is used in psychotherapy, most often to treat certain phobias and bad habits such as overeating and smoking, but has proven unsatisfactory in dealing with true addictions such as drugs or alcohol. 4,30

Therapeutic hypnosis was practiced by many nineteenth century physicians, including Dr. Jean Martin Charcot, the father of clinical neurology and one of Sigmund Freud’s teachers. In fact, Freud began his exploration of the psyche by hypnotizing his patients, but eventually replaced this approach with free association, his key to the unconscious mind. 30

As for the testing methods developed during the mesmerism inquiry, the Franklin commission established a new strategy for assessing the validity of controversial claims about therapeutic effectiveness: the single-blind placebo-controlled clinical trial. The use of placebos did not start with the Mesmer inquiry, of course. One could argue that before the discovery of the foxglove (digitalis) plant’s benefit on dropsy (congestive heart failure) virtually all medical prescriptions depended for success on a combination of natural healing and the placebo effect.

The path of intentional sham treatment for the purpose of clinical inquiry led from the Franklin commission’s experiments to a 1799 investigation of the Perkins Tractor done in England by Dr. John Haygarth. 18 Several years earlier, Elisha Perkins (a Connecticut physician) invented a medical device consisting of two metal rods, one made of iron and the other of brass, each approximately 3 inches long, bulbous at one end and pointed at the other (Fig 4). 21 When stroked over an afflicted body part, the rods allegedly conducted away disease-causing electroid fluid. Haygarth expressly followed the experimental design of the Franklin inquiry to expose Perkins’ claims. In one experiment, Haygarth used a placebo pair of wooden rods painted to look like metal. He wrote, “. . . prepare a pair of false, exactly to resemble the true, tractors. Let the secret be kept inviolate . . . Let the efficiency of both be impartially tried.”

Fig 4.
Fig 4.:
Perkins tractors, each approximately 3 inches long, made of dissimilar metals, were invented to draw away poisonous electroid fluid from diseased body parts.

In another evaluation, Haygarth insulated the rods with a wax coating, eliminating their conductivity, while he purposefully kept the subjects ignorant of the modification. Haygarth concluded that “The whole effect undoubtedly depends upon the impression which can be made upon the patient’s Imagination.”18

Within a few decades came numerous placebo-controlled inquiries, in Europe and America, into the professed benefits of Hahnemann’s homeopathic remedies specifically citing the mesmerism inquiry. Other blind assessments followed, scrutinizing everything from rheumatic fever and psychologic illnesses to testicular extract injections and cocaine. 21

The final step in creating a thoroughly modern method of verifying the benefit of a particular treatment followed statistician Fisher’s insistence that randomly assigning subjects to a treatment group or a control (placebo) group permits valid statistical comparisons between the two groups to some definable level of confidence (the p value). 8

Medical doctors often decry the cures claimed by certain allied health professionals such as chiropractors and acupuncturists, as being a consequence of the practitioners’ enthusiasm for the treatment, projected unto believing patients. Haygarth also recognized the importance of the treater’s confidence in the regimen. He warned, “If any person would repeat these [Perkins’ Tractor] experiments, they should be performed with due solemnity . . . The whole effect depends upon the impression which can be made upon the patient’s Imagination . . . Any enthusiastick dupe of this doctrine can perform cures with incomparably greater success than the most skillful physician or surgeon . . . Genuine enthusiasm is wonderfully infectious.”18

Physicians and surgeons fail to recognize that they sometimes achieve clinical success through such infectious enthusiasm. Although the double-blind, placebo-controlled randomized clinical trial is considered the gold standard for evaluating the alleged value of newly developed pharmaceuticals and devices, assessing the claimed advantage of new surgical procedures, has, for obvious reasons, not been as easy. 16 The same can be said for certain long-established therapeutic practices derived from an ancient healing art such as bonesetting. 15

There has been a tendency of late to accept and promote alternative medicine protocols which, in many ways, resemble the debunked cures of bygone days. Likewise, many operations for the treatment of chronic pain emanating from musculoskeletal structures, shoulder, knee, foot, that have proven successful when done by some surgeons but not others. Clearly, a surgeon’s belief in a procedure’s value may be transferred easily to a patient, leading to cures not easily obtained by more skeptical practitioners.

The placebo-controlled single- or double-blind randomized clinical trial remains the most reliable method of assessing the claimed benefits of any therapeutic intervention. Although it may be difficult to design and conduct such investigations in some settings, every effort should be made to do so.

By being part of an investigation that pioneered the most reliable way to judge the efficacy of a wide variety of drugs and devices, Franklin, Lavoisier and their fellow commissioners set in motion a process that has led to great advances in medical therapeutics. Concurrently, blind assessment and sham intervention has put to rest many bogus treatment claims. Such inquiries, however, take time and effort. As the Franklin commission report put it, “Had the commissioners . . . neither the time nor opportunity of making decisive experiments, they might themselves been led into error. It was necessary to insulate the effects in order to distinguish the causes . . . Such an examination demanded a sacrifice of time, and a number of systemical researches . . .”9

Acknowledgments

The author thanks Elizabeth Ihrig of The Bakken Museum and Library for assistance in obtaining copies of historic documents.

References

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