Many people will remember Dr Bill Morris’s entertaining autobiographical talk at the last Skeptics’ conference in Wellington. From his presentation, we extract this discussion of what is still the most persistent and potent medical effect known to the human race.
The word “placebo” may or may not be recognisable to you as being of Latin origin, from the verb placeo, placere, to please, and placebo is the first person singular of the future indicative tense, or “I shall please.” Its first recorded use in the English language was in 1225 in reference to Vespers in the Office for the Dead, and the word was derived from the first word of Psalm 116 v 9 “Placebo Domino in regione vivorum.” This is usually translated as “I shall walk before the lord in the land of the living,” but as the Vespers for the dead was in effect a request for the dead to intercede with God for the benefit of the living, it is better translated as “I shall please or intercede with God on behalf of those in the land of the living.”
By 1386 it had appeared in Chaucer’s Merchant’s Tale to mean a flatterer and by 1811 it had acquired one of its modern senses as “…an epithet given to a medicine adapted more to please than to benefit the patient.”
It may surprise you to learn that it was as late as 1938 before the word appeared in its other modern sense, that of a dummy medication used as a control, and probably the first well documented randomised placebo controlled trial was that of streptomycin for the treatment of tuberculosis of the lung, in 1948.
The Medical Research Council pointed out that the natural history of tuberculosis of the lung was so variable that “evidence of improvement or cure following the use of a new drug in a few cases cannot be accepted as proof of the effect of that drug” by contrast with tuberculous meningitis which was invariably fatal without treatment.
The placebo treatment was bed rest alone, whereas the streptomycin group received both bed rest and streptomycin. In this instance the patients obviously knew they were getting streptomycin as it has to be given by injection, but the progress of the disease was followed on chest X-rays which were assessed without knowledge of which treatment the patients had received.
Ethical considerations did not apply, as the only possible alternative treatment at that time was bed rest, and in any case only limited amounts of streptomycin were available. Nearly forty five years on, it is difficult to accept that bed rest alone was perceived to be an effective treatment.
By 1950 the Journal of Clinical Investigation wrote, “It is customary to control drug experiments on various clinical syndromes with placebos, especially when the data to be evaluated are chiefly subjective.” and so by this date, the use of dummy medication in drug trials was firmly established.
It soon became clear that many people reported side effects or improvement when receiving placebos in trials and it soon became possible, though perhaps not useful, to say that the placebo effect was that which all treatments have in common. Perhaps more useful is to combine the two definitions and say that it is a non-specific effect of a treatment attributable to it but not to its pharmacological properties.
Any form of treatment can act as a placebo, and the strength of the reaction varies with the supposed potency of the treatment so that a capsule is better than a tablet, an injection is better than a capsule, an injection that stings is better than one that doesn’t and an operation is even better than an injection that stings.
In 1939 it was suggested in Italy that tying off the internal mammary arteries could greatly reduce the pain of angina pectoritis. The operation eventually became fashionable in the USA with quite spectacular results. The patients said they felt better and there was objective evidence to support this in that they could walk further and their consumption of angina pills decreased.
Eventually a double blind controlled study was done in which half the patients had their internal mammary arteries tied and the other half simply had them exposed without tying them. Neither the patients nor those who assessed them knew until the study was completed who belonged to which group. It turned out that ligation had no greater effect than the dummy operation. Since ligation of the internal mammary arteries was quite a major operation with potential for harm as well as good, and there was genuine doubt that it was useful, not only was the trial ethical, but it would have been unethical not to have done it.
Placebos can also cause toxic effects just like those of an active drug, and in a study of 25 patients given placebos, ten reported sleepiness, nine palpitations, eight irritability, five weakness with a fall in blood pressure of more than 20 mm of mercury, four reported diarrhoea, two collapse and two itching. Three of the patients also developed dependence on the placebo (lactose) and had withdrawal symptoms when it was stopped.
Now one suspects that if we stopped people in the street at random they might report a similar rate of these symptoms, and at the 1992 Skeptics Conference, on asking for a show of hands, I found that the proportions enjoying the symptoms listed above were greatly exceeded.
As soon as the placebo effect became clear, investigators began to look for factors which might identify the placebo responder in the hope that eliminating them from the studies would make the data much clearer.
A variety of psychological studies has been done but there are so many inconsistencies among the results that one can conclude that there is no single personality trait that characterises the positive placebo reactor, with the possible exception that stress or anxiety has been rather consistently associated with placebo reactivity. Expectation has been cited as a possible mechanism.
In one study, experimenters were told that their rats had been bred especially either for intelligence or dullness, although in fact all the rats were from the same genetic strain. The experimenters then performed learning experiments on the rats and obtained results that conformed to their expectation.
Brody cites this as possible support for the idea that if experimenters can somehow communicate their expectations of the rats’ behaviour to the rats “It seems reasonable to assume that physicians can unknowingly communicate their expectations and attitudes to the patients, altering the patients’ therapeutic outcomes as a result.” My own view is that old Procrustes is at it again, altering the accuracy of the experimenters’ observations rather than the rats’ behaviour.
Theories of placebo action have been largely psychological or psychoanalytical, but a reductionist like myself sees behaviour, feelings, thoughts and so on in terms of as yet poorly understood physico-chemical activities in the brain and peripheral nervous system, rather than as something happening somewhere in a bubble marked “psyche.” A little support for this view comes from a randomised double blind placebo controlled study by Levine and others into the mechanism of pain relief following extraction of impacted lower wisdom teeth. A third were given naloxone, a substance which is believed to inhibit the action of naturally occurring pain relieving substances in the brain called endorphins, a third were given a placebo and a third were given morphine. Those given naloxone reported significantly more pain than those given the placebo.
Levine hypothesised on this basis that placebo pain relief is mediated by endorphin release, but as Skrabanek pointed out later, they did not test their hypothesis by actually measuring endorphin levels, and in any case the results were exactly what might be expected if the naloxone were acting as a placebo itself. The paper was also severely criticised by Korczyn, but nevertheless it continues to be quoted quite extensively as “demonstrating” that pain relief by placebos is mediated by endorphins, a claim, incidentally, that is also made for pain relief by acupuncture.
We simply do not know why about thirty percent of patients experience relief of symptoms when given a therapy that cannot be expected to have any effect. In a sense, the history of medicine up to about 1950 is largely the history of placebos. We may find it amusing to look at some of the truths of yesterday which are the falsehoods of today, like the fashion for enemata in eighteenth and nineteenth century France. Sometimes enemata even of tobacco smoke were administered, and while we cannot feel entirely confident that the Tobacco Institute would disapprove of this, we can feel sure that many of our present day medical practices will appear stupid and ignorant to our great grand-children.
For the last forty five years we have had the means to set a limit to our errors, and yet colleagues tend to set store by anecdotes and case series which are in truth little better than a succession of anecdotes. The results of poorly designed case control studies continue to be accepted without proper caution. If physics is the queen of the sciences, then the randomised double blind placebo controlled study is the queen of medical investigation, though for events that occur relatively rarely, cohort studies and case control studies are inevitable second and third best choices.
People, including I am sad to say, doctors, have said to me “What does it matter whether a treatment is a placebo or not as long as it works? Surely the thing is to cure the patient and when you cannot cure, to comfort.” I can certainly agree with the aim, but not that it does not matter how we do it. If we do not make sure of the truth then we shall not be able to separate the wheat of science from the chaff of falsehood, and as Berthold Brecht put it, the aim of science is not to open a door to infinite wisdom, but to set a limit to infinite error.