Sunday 5 October 2014

A Brief History of the Placebo Effect

The statistics student is often introduced to the term placebo without much information about how they came about. They often assume that clinical trials stared with Francis Bacon, or some other early "father" of the scientific method.
For students and teachers who have not had the opportunity to read up on it, here is a brief history of some aspects of the evolution of the placebo and the placebo effect.

First a bit of etymology. The word placebo (Latin, 'I shall please') was first used in the 14th century. In that period, it referred to hired mourners at funerals. These individuals often began their wailings with the ninth verse of psalm 114, "Placébo Dómino in regióne vivórum". This is the Latin for, "I will please the Lord in the land of the living". From that, a singer of placebo became associated with someone who falsely claimed a connection to the deceased to get a share of the funeral meal(or occasionally money from the real family), and hence a flatterer, and so a deceptive act to please. Around the same time, in the late 1300s, Geoffrey Chaucer in his Canterbury Tales (Merchant's Tale, probably not one to read from in class) uses Placebo as the name of the sycophantic brother(or friend) of the protagonist (by contradiction, his other featured friend is Justinus - 'the just one').

The first documented medical use of the word placebo dates from the late 18th century. In the 1785 New Medical Dictionary, placebo is described as 'a commonplace method or medicine'

An interesting story of a placebo like substance, was the use of "powder of sympathy" in the 1700's to heal wounds. The powder was applied to the weapon that caused the wound (or a similar stand-in where the actual weapon was not available) in order to achieve the healing. It seems that often the method was very effective and the injured recovered. This may have been because of the unsanitary conditions of medical treatment at the time, making it safer NOT to have the doctor treat you.

Until the first half of the 20th century the use of placebos seems to have been widespread in medicine. In the practice of medicine it had been long understood that, as Ambroise Paré (1510–1590) had expressed it, the physician’s duty was to "cure occasionally, relieve often, console always".

In 1807 Thomas Jefferson, recording what he called the pious fraud, observed that "one of the most successful physicians I have ever known has assured me that he used more bread pills, drops of colored water, and powders of hickory ashes, than of all other medicines put together". About a hundred years later, Richard Cabot, of Harvard Medical School, described how he "was brought up, as I suppose every physician is, to use placebo, bread pills, water subcutaneously, and other devices."

Clinical trials using a control group or a placebo were not common until the second half of the 20th Century. Most therapies were judged to be efficacious on the basis of pathophysiological rationales provided by authoritative experts rather than by documented observations and comparative research. The bulk of clinical knowledge was based on noncomparative research, though there are some exceptions.
In 1747, James Lind (1716–1794), the ship's doctor on HMS Salisbury, conducted the first clinical trial when he investigated the efficacy of citrus fruit in cases of scurvy. He randomly divided twelve scurvy patients, whose "cases were as similar as I could have them", into six pairs. Each pair was given a different remedy. According to Lind’s 1753 Treatise on the Scurvy in Three Parts Containing an Inquiry into the Nature, Causes, and Cure of the Disease, Together with a Critical and Chronological View of what has been Published of the Subject, the remedies were: one quart of cider per day, twenty-five drops of elixir vitriol (sulfuric acid) three times a day, two spoonfuls of vinegar three times a day, a course of sea-water (half a pint every day), two oranges and one lemon each day, and electuary, (a mixture containing garlic, mustard, balsam of Peru, and myrrh). He noted that the pair who had been given the oranges and lemons were so restored to health within six days of treatment that one of them returned to duty, and the other was well enough to attend the rest of the sick.
In 1801, John Haygarth reported the results of what may have been the first placebo-controlled trial. A 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 electromagnetic influence of the metal. Haygarth treated five patients with imitation tractors made of wood and found that four gained relief. He used the metal tractors on the same five patients the following day and obtained identical results: four of five subjects reported relief. It is clear that Haygarth had the notion of a placebo effect when he stated that "an important lesson in physic is here to be learnt, the wonderful and powerful influence of the passions of the mind upon the state and disorder of the body. This is too often overlooked in the cure of diseases". He further wrote that the experiment 'clearly prove what wonderful effects the passions of hope and faith, excited by mere imagination, can produce on disease'. In fact, Haygarth had not abandoned the Renaissance idea that imagination was the major mediator between body and mind.  The image Caricature of a quack treating a patient with Perkins Patent Tractors by James Gillray, 1801 from Wikipedia.

In the beginning of this century, the German physician Adolf Bingel performed a large-scale comparative clinical trial to assess the specific effect of diphtheria antitoxin serum in the treatment of diphtheria. Bingel was concerned whether the antitoxin in the serum was responsible for the effect or whether treatment with serum not containing the antitoxin would give comparable results. He alternately allocated 937 patients to either diphtheria antitoxin serum or normal horse serum (the placebo) and assessed the effect. He concluded that treatment with normal horse serum achieved a similar clinical outcome to that with the antitoxic serum.

In modern times, T. C. Graves first defined the "placebo effect" in a published paper in The Lancet in 1920. He spoke of "the placebo effects of drugs" being manifested in those cases where "a real psychotherapeutic effect appears to have been produced".

In 1938, the word placebo was first applied in reference to the treatment given to concurrent controls in a trial. In previous years, uncontrolled observations had given promising results with vaccines in preventing colds. Controlled experiments, with persons in the control group receiving no treatment, had also given favorable results. The efficacy of cold vaccines was evaluated in several placebo-controlled trials. The authors reported that
'the students in the control groups were treated in exactly the same manner as those in the experimental groups but received placebos instead of vaccine. The subjects in this group were given lactose-filled capsules which were indistinguishable from the capsules contain- ing the vaccine. They were prescribed with exactly the same instructions as the capsules containing the vaccine.'
The trial gave negative results, although the results in the vaccine-treated groups were comparable with those in previously reported experiments. It was the substantial improvement in the placebo group that made the findings negative. The conclusion reads
'one of the most significant aspects of this study is the great reduction in the number of colds which the members of the control groups reported during the experimental period. In fact these results were as good as many of those reported in uncontrolled studies which recommended the use of cold vaccines'.

In 1961 Henry K. Beecher found that surgeons he categorized as enthusiasts relieved their patients' chest pain and heart problems more than skeptic surgeons. Beginning in the 1960s, the placebo effect became widely recognized and placebo controlled trials became the norm in the approval of new medications.

Although the placebo effect and theories on its underlying mechanisms are mostly understood in terms of human psychology, studies have also indicated that non-human animals such as dogs can also have symptoms reduced by placebo treatments.

In 1961 Walter Kennedy introduced the word nocebo to refer to a neutral substance that creates harmful effects or reactions in a patient who takes it.

The word obecalp, "placebo" spelled backwards, was used by an Australian doctor in 1998 when he recognized the need for a freely available placebo. The word is sometimes used to make the use or prescription of fake medicine less obvious to the patient. The word "Obecalp" was actually in common use but not published much earlier than 1998 . For example, a prescription for "Obecalp #3" was written in 1978 in Marysville California by a California Emergency Physician for a patient with a history of repeated visits by ambulance to the Emergency Department for pain and anxiety related symptoms. These visits stopped for one year after she received a prescription for thirty Obecalp #3 tablets (glucose tablets) that was refilled monthly for 12 months. The use of the backward spelling of "placebo" for this prescription was chosen to allow multiple physicians caring for her to quickly understand that it was a placebo.

I have quoted large portions of the material above from "Placebos and placebo effects in medicine: historical overview" by Anton J M de Craen PhD, Ted J Kaptchuk OMD, Jan G P Tijssen PhD, J Kleijnen MD PhD2 interlaced with notes from Wikipedia and my own notes from many years of teaching.

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