Estudio legal NOM-070-SCFI-1994

“You should treat as many patients as possible with the new drugs while they still have the power to heal.”

TROUSSEAU

The response of patients to placebo varies. The patient’s anxiety, perception of the physician, expec-tations, and prior experience of the treatment affect his or her response. As Trousseau wrote long ago, enthusiasm for a new or unfamiliar treatment can accentuate the reaction. Interestingly, patient

compli-ance is also associated with a positive placebo response. In a study of patients taking a drug to lower cholesterol, those who took their pills regularly had a reduced mortality rate in both the active and placebo treatment arms of the trial.⁵³

Most published placebo research suggests that every human ill responds to placebo, at least tran-siently. Pain is particularly responsive to placebo, as are diseases that have an erratic clinical course.

Human case reports and animal studies indicate that even serious diseases appear to respond to placebo.

Unfortunately, some misguided physicians have erro-neously convinced themselves that a patient’s response to placebo is proof that the patient did not have a “real” medical illness. Few doctors believe such reasoning has any role in the ethical practice of med-icine.

The placebo response occurs in every clinical encounter. The evidence suggests that every clinical interaction has the potential for an entire spectrum of patient response, ranging from wonder-fully beneficial to extremely harmful. Clinicians have a professional obligation to recognize this potential.

We must carefully avoid interactions that harm the patient as we strive to help to the best of our ability.

Some research supports the idea that transience is a characteristic of placebo response. Benson and McCallie’s angina work⁴⁵and a few other studies sug-gest otherwise. To those who prefer a world ruled by common sense, proof that placebo effects are transient would provide a mind-settling confirmation of placebo’s ephemeral nature. In addition, a pattern of fleeting response could become the key to distinguish-ing placebo effects from the “real” effects of active treatment. Only time and further research will tell.

Adverse Effects of Placebo

Another false belief about placebo, a belief that is par-ticularly relevant to homeopathy, concerns adverse effects. Some have claimed that one of the proofs that the effects of homeopathic treatment are not solely attributable to placebo is that homeopathic remedies can cause adverse effects. Homeopaths accept that the correctly chosen homeopathic remedy for a chronic condition is likely to create a transient exacerbation of symptoms. The term aggravation is used to describe this process. The aggravation con-cept is so well accon-cepted that homeopaths sometimes express concern that the correct remedy was not given if an aggravation does not take place.

However, the ability to produce adverse effects does not prove that homeopathy is more than placebo, because placebos can generate adverse effects. Before discussing adverse effects created by placebo, it is important to distinguish adverse placebo effects from nocebo effects. Nocebo, which means “I shall harm,” is the true opposite of placebo.

Nocebo effects are those that result from negative expectations. In other words, a patient expects some damaging effect from an inactive treatment and the expectation leads to the undesired outcome. One of the most famous studies in placebo literature is an example of the power of nocebo. In 1975, Ader and Cohen released a study regarding the administration of cyclophosphamide mixed in saccharin water to rats.⁵⁴While tracking the rats’ death rate following ingestion of this combination, Adler and Cohen dis-covered that even when cyclophosphamide was no longer administered, rats receiving saccharin alone continued to die as if they were still suffering the ill effects of the cyclophosphamide.

Rats are not alone in their vulnerability to placebo or nocebo. Conditioned nocebo effects also occur in human beings. Various reports, usually unsubstantiated, of “voodoo death,” in which a per-son dies after having been the subject of a curse placed by a powerful member of the community, have been a part of the lore of placebo for genera-tions. There have been a number of recent reports of mass hysterical-symptom outbreaks following per-ceived (but subsequently disproved) exposures to toxins.

Adverse effects from placebo are unexpected, undesired reactions to treatment. The patient’s high hopes are disappointed or accompanied by additional unforeseen unpleasant effects.

The previously cited study by Shapiro and associ-ates⁴⁷ found that more than half of a group of patients taking placebo to improve their general health experienced adverse effects of some sort.

Interestingly, Shapiro also found that patients who did not benefit from the placebo also did not experi-ence any adverse effects. In other words, not only do adverse effects occur, but they often appear to be an integral part of the placebo response.

Another viewpoint considers the issue of placebo irrelevant. The patient’s beneficial response to a treatment is important. The means to that end is not.

This view is most commonly that of clinicians and, of course, patients themselves. A recent Lancet editorial

advocated more research into this aspect of the placebo:

Second, perhaps there should be more investigations into the role of placebo, not as a confounding factor interfer-ing with study design, but as a method of enhancinterfer-ing the efficacy of and reducing the variable response to anal-gesics and other methods of pain control.⁵⁵

Carrying the idea of patient benefit as the physi-cian’s primary ethical duty further, some believe that raising the specter of placebo might have unethical repercussions. Discussing the concept of placebo could be harmful to the patient, because acknowl-edging the possibility of placebo treatment alters the interaction with the patient. The possibility that the treatment might be placebo can reduce the response to an effective nonplacebo treatment.⁵⁶

Placebo effects are not restricted to inactive treat-ments. They also augment effective ones.⁵⁷In a study by Skovlund, women who had just given birth were treated for postpartum uterine pain.⁵⁸ In the first phase, fol-lowing an informed consent procedure, they were given either paracetamol or placebo. In the second phase, con-ducted immediately afterward, a new group of patients on the same hospital ward were randomly given parac-etamol or naproxen knowing they might receive either medication. Interestingly, the effect of the paracetamol in the second trial was markedly enhanced, apparently by the patients’ knowledge that they were certain to receive active treatment (Figure 6-2).

Although complementary medicine is certainly not entirely placebo, placebos appear to be a form of com-plementary medicine, because their effects augment the effectiveness of conventional medicine. Conversely, the knowledge that he or she might not be receiving an effective treatment diminishes a patient’s expectations and therefore the clinical response. One could argue that it is the ethical duty of the physician to set aside doubts about the effectiveness of a treatment and administer treatment with a full measure of conviction to maximally benefit the patient.

Limitations of Placebo in Research

Although these concepts have many repercussions for clinical medicine, the challenges created for researchers are no less significant.⁵⁹Distinguishing a treatment from placebo is the usual objective of clin-ical trials. Although this is a difficult task, it is often by itself insufficient to meet the needs of patients and clinicians.

Because placebo can be effective treatment for many patients, its power must be recognized and respected. When placebo’s power is respected, com-paring a treatment to placebo becomes a considera-tion of the degree of effect as well as the frequency and nature of adverse effects.

Statistical superiority over placebo can be mis-leading. Some homeopathic trials have been criticized on this basis. A difference that is statistically signifi-cant but not clinically meaningful to the patient is irrelevant to that patient and his physician unless there is some other compelling advantage, either in the adverse effect profile or cost of the treatment.

It is clear that an important limitation of RCTs is the issue of clinical relevance—sometimes the patient is forgotten in clinical research. Researchers who are primarily interested in measuring quality of life have come to believe that the patient’s well-being is the ultimate outcome measure.⁶⁰ In addition, there is some evidence that the patient’s opinion might be the best discriminator between placebo and active treatment.⁶¹It is essential that the patient never be forgotten in research as well as in clinical medicine.

Pain intensity

Time Paracetamol 2 Naproxen 2

Paracetamol 1 Placebo 1 Paracetamol 2

Paracetamol 1 Naproxen 2 Placebo 1

Time 0 0 0 0

2 Hours 40 30 20 3

4 Hours 38 29 18 2

Figure 6-2. Effect of expectation on pain relief.

Lessons from Placebo and