

Unit 3: Introduction

Case 1: Face-Off: Cosmetic Treatment or Damaging Experiment?

Case 2: The Pernkopf Atlas: The Dilemma of Tainted Data

Case 3: Atomic Testing at Bikini Island: Innocent Bystander Islanders and Soldiers

Case 4: Genie, The Wild Child: Research or Exploitation?

Case 5: Walter Reed's Yellow Fever Studies: Roots of Informed Consent

Case 6: Risky Business: Treating the Potential for Diseases

Case 7: Untreated Syphilis: Mistreated Men

Case 8: Placebos and Placebo Effects

Timeline: Significant Events in Human Subjects Research

Case 8 Placebos and Placebo Effects Placebos are dummy treatments. Doctors of old prescribed them for demanding patients who wanted some sort of pill or injection for their illnesses. A typical placebo might be a pill containing only sugar or bread or an injection containing only salt and water, and a placebo "sham" operation was one in which the patient was cut open and then sewn right back up. All of these so-called dummies were given to placate the patient, not to fix the illness-hence the Latin name placebo, which means "I shall please."



In the early 1950s, researchers began using placebos as controls in most clinical studies. They would compare the effects of a new pill, for example, with those of a placebo pill that looked exactly the same but had no known active ingredients. Placebos established a baseline, showing, for example, the effects of pill-taking per se. If the placebo pill worked as well as the new pill, then the active ingredients in the new pill weren't all that active. The experiments typically were carried out "double blind": neither the subjects who were participating in the studies nor the researchers who were conducting them knew who was getting which pill.



Many clinical trials no longer include placebo controls. Instead, the controls might be an available treatment that is partly effective but not quite good enough, the current standard therapy in a range of doses, several doses of the new test therapy, or no treatment at all.



Here are examples of three clinical trials in which the use of placebo controls has raised complex ethical questions.



Treatments For Aids In Africa AIDS is always a fatal disease. It is caused by the human immunodeficiency virus HIV. Newborns whose mothers are infected with HIV can acquire the infection from their mothers at the moment of birth. In some African countries, more than 30% of pregnant women who are examined at perinatal clinics are infected with the AIDS virus.



Clinical trials in 1994 showed that, if a pregnant woman took the drug AZT in pills during the last 12 weeks of pregnancy and as an injection during labor and if the baby received AZT during the first six weeks of life, the baby had a much-reduced chance of becoming infected with the virus. Since that time, in the United States, pregnant women infected with HIV are advised to use this "076 regimen" of AZT.



Thus, an enormous public outcry arose in 1997 when American and African researchers gave a placebo, rather than AZT, as a control to pregnant women in Africa who were infected with HIV and were participating in clinical trials. The researchers argued that "standard" treatments for AIDS for these women were no treatments at all. (The 076 regimen, for example, was simply too expensive for women and governments in poor countries, costing between $800-$1000 per person.) The researchers were evaluating lower and fewer doses of AZT in the studies to see if low doses might be effective. Such doses might be affordable and accessible for the African women (and other poor women around the world). The researchers argued that placebo controls were appropriate, that they constituted the local "standard" therapy, and that they would provide answers faster than would other types of controls.



Some people argue that it is unethical to use different standard treatments for rich and poor women. Others say that western researchers should not impose "ethical imperialism" on women in other countries and that each country should determine its own standards for what is ethical in research. Still others argue that, because placebo trials end more quickly than do trials in which different doses of AZT are compared and because placebo trials use fewer subjects than do other trials, in the long run, more children would be saved through placebo trials. Still others counter that no person should be a means to an end, however positive that end might be.



Placebo Effects Placebos are said to be dummies-dummy pills, injections, surgeries, and other treatments. The pills and injections contain no known active ingredients, and the surgeries do nothing-they involve an incision and its repair.



But, one of the oddest phenomena in medicine is that, about 30% of the time, placebos actually work as well as the treatments they are compared with in clinical trials. No one knows why this is so. The "placebo effect" is an authentic, active effect for a range of diseases and conditions-nausea, various types of pains, coughs, headaches, anxieties, colds, diabetes, ulcers, depressions, and even some psychoses.



Placebos also can cause nasty side effects, the so-called nocebo effects, for "I shall harm." Nocebo effects are less common than are placebo effects but are still well documented.



What accounts for placebo (and nocebo) effects?



Many studies suggest that, for certain individuals, an encounter with a doctor or other healer is enough treatment to initiate a recovery. The doctor may write a prescription, but the patient recovers even without filling it. Or the patient will feel better after undergoing a series of diagnostic tests. One explanation for placebo effects is that the hopefulness that the patient feels while being treated translates into a physiological surge of specific hormones and other biochemicals in the body. These then go on to trigger therapeutic immune responses. One class of hormones implicated so far is the endorphins. They carry messages from the nervous system through the bloodstream to the endocrine and immune systems where they induce the production and release of other biochemicals that contribute to healing.



The contemporary western 'medicine cabinet' is filled with active drugs and injections and other treatments. But, one hundred years ago, doctors had many fewer 'specifics' for treating disease. Richard Cabot, a turn-of-the-20th-century doctor wrote that he "was brought up, as I suppose every physician is, to use placebos, bread pills, water subcutaneously and other devices acting upon a patient's symptoms through his mind."



If placebos actually work, why don't doctors just prescribe them for their patients? At what point is it medically appropriate for a doctor to conclude that a placebo is the best 'therapy' for a patient?



Sham Surgery Surgery is always dangerous, always 'invasive.' So, with every surgical procedure, the patient considers whether the benefits will outweigh the risks and then decides whether to proceed or not.



Doctors performed placebo or sham surgeries for many years. But, by the 1970s, most sham surgeries were stopped. Today, their use in medical research is on the rise. The advocates argue that surgery, like new drugs, should be submitted to rigorous, well-controlled studies.



How do the risk-benefit scales tip for placebo surgeries?



Recent studies of experimental treatments for Parkinson's disease included sham surgery controls. Surgeons drilled four tiny holes through the foreheads of forty patients, creating portals into their skulls. Then, half of the patients received injections of fetal cells; the others got nothing. The hope was that the fetal cells would repopulate the brain, replacing damaged and lost brain cells with active, functional ones.



The subjects knew that they had a 50:50 chance of receiving nothing or receiving the fetal cells. They were also told that, if, after one year, the fetal cells proved helpful to the people who got them, all people in the study would be given injections of fetal cells.



At the end of the year, the results were ambiguous. Those who received the fetal cells were not clearly better off than those who had the sham operations. The researchers and the oversight committee chose to wait another year or two to see if the fetal cells would be therapeutic. Some subjects in the placebo group were furious. They wanted their promised injections of fetal cells, even though the cells' effectiveness was unproven. Several said that they would not have entered the study had they known that they would not get the cells eventually.



Included References AIDS New England J Med 1997 September 18 337(12):853-856. Placebo Effects Scientific American 1998 January 90-95. Sham Surgery New York Times, April 25, 1999, WK3, Stolberg. Wall Street Journal, Dec. 11, 1998, A1, Johannes. Additional Resources Classic Cases in Medical Ethics, Gregory Pence, 3rd edition, 2000, 274-276 (AIDS) Aims Students should understand the following: Placebos and nocebos

Placebo effect

Standard treatment

Ethical imperialism

Economic issues in health care

Role of hope in medicine

Sham surgery

Fetal cells as therapy for Parkinson's disease

Therapeutic misconception Suggested Questions for Discussion Should the same ethical standards apply to American women and African women with respect to placebo studies of drugs for AIDS? Why? What about women in all other countries? What are the ethical arguments against harming one patient today (in a trial?by withholding therapies, such as was done in the AIDS trial) with the possibility of helping millions of persons in the future? Does the number matter or is harm the issue? Should people be treated as means to an end when the end is an important one? One physician (Thomas Freeman) who conducted some of the placebo-controlled trials with fetal cell brain implants said "Ultimately, I decided it's more ethical to put 12 patients through an imitation operation than have thousands go through operations, claimed to be efficacious, that actually kill more people than they help." Is this sort of ethical decision one that a single surgeon should make or is this a subject that should be addressed by a committee of some sort? Who should be on such a committee? What issues should they consider? Why are placebos acceptable as controls in some experiments for diseases for which there is no known treatment? Why are they less acceptable for diseases for which some form of treatment exists? If volunteers are willing to accept some risks, is it paternalistic for doctors or IRBs or other oversight committees to say that the risks are unacceptable? Is research designed to benefit patients or to further medical research? What is the distinction? How does this lead to false hopes in some research subjects? What happens when researchers focus more on data than on subjects? If dummy drugs and dummy operations can actually help patients 30% of the time, why don't doctors prescribe them instead of prescribing active drugs and operations? The French philosopher Voltaire once wrote that "the art of medicine consists of amusing the patient while Nature cures the disease." How does this remark relate to the placebo effect? The Hippocratic Oath, sworn by all doctors, includes the command "to apply all existing knowledge for the best possible treatment of individual patients." How does the use of placebos fit (or not) with this obligation? Sometimes the greatest placebo effect comes from an encounter with a doctor. If that is the case, what will happen to placebo therapy in the 'new' medical environment in which patients and doctors rarely meet one another? Topics for Discussion/Written Assessment How might researchers decide whether to use placebo controls in clinical trials? When are placebos appropriate? When is a standard treatment a more suitable control?

How risky are placebo treatments? What might the risks be in pills, injections, surgical procedures? At what point are the risks greater than the benefits of placebos?

What is a double-blind experiment? Why are experiments done this way?

In America, pregnant women who are infected with HIV are advised to take AZT during pregnancy and to refrain from nursing their babies. What cultural factors make these recommendations inappropriate for some African women? (Some answers: When women in Africa discover that they are infected with HIV, they may be beaten or ostracized by the family. Because they do not want to reveal that they are infected, they may be unwilling to take drugs for AIDS. They also may not be willing to refrain from nursing, which is standard practice in the culture. In addition, if babies in Africa are not nursed, they will not be protected from a range of tropical diseases-malaria, schistosomiasis, and so on-that can also be fatal.)

What is the role of hope-for patients, for doctors-in medicine? Extension Questions for Further Investigation What parallels and differences can you identify in how the women in the AIDS studies in Africa were treated and how the men in the syphilis experiments were treated? Are placebo-controlled AIDS studies still going on in Africa or in other countries? If yes, where are these studies being done, what groups are involved, and what are the results? In 1998, researchers found that AZT therapy costing $80 per person could reduce the transmission of HIV to babies in Thailand by 50%. Pregnant women took the drug only during the last four weeks of pregnancy and during labor and delivery. Find out whether this therapy proved to be cheap enough to help substantial numbers of women and their babies in poor countries where AIDS is endemic. What are endorphins? What are their roles in placebo effects? Investigate the "therapeutic misconception." How does it occur in clinical trials? (TM: that experiments are beneficial and therapeutic even in the earliest stages. Even though people give consent and say they are informed, they often do not really understand how likely they are to not reap any benefits from a trial.) What are the phases of clinical trials? What are the differences in what can happen at each phase? After biologist Robert Koch and his contemporaries of the late 19th century showed that bacteria, viruses, and other organisms actually produced certain infectious diseases, they were in a position to design specific therapies to counter the activities of the disease-causing organisms. At that point, placebos were no longer appropriate as treatments. What were the steps that Koch outlined-called Koch's Postulates-to prove that a specific organism caused a specific disease? In the 1980s, infant formulae made by the Nestle Corporation were associated with the failure of many American infants to thrive. After Congressional hearings, the company withdrew the cans of formula from grocery shelves and sent the cans to Africa. Women there used the formula, mixing it with contaminated water, which made even more children sick. What are the ethical issues raised by Nestle's activities? Topics for Teacher Preparation Placebos, placebo effects, nocebos

Ethical imperialism

AIDS and treatment options in industrialized and poor countries

Maternal-to-fetal transmission of AIDS

Sham surgery

Physicians' obligations to patients

Risk-benefit ratios

Parkinson's disease trials with fetal cells

Role of hope in medicine

Therapeutic misconception (that a trial is a treatment)

