THE meaning that placebos have had for health care providers has swung like a pendulum through the ages - from magical cureall to disparagement to a current hard look at the biological and psychological aspects of this phenomenon. What exactly is their status in today's medical and research world? The word placebo derives from the Latin term "to please." The concept of a placebo comes from medieval times, when professional mourners were paid to stay by the bedside of. deceased person, reciting a psalm beginning "Placebo Domino..." or "I shall please the Lord." "Placebo" gradually became the word used for the paid mourner, whose grief was, in fact, false. In modern medical terms a placebo has come to mean "the psychological, or psychophysiological effect of any medication or procedure given with therapeutic intent, which is independent of, or minimally related to, the pharmacological effects of the medication or to the specific effects of the procedure, and which operates through a psychological mechanism." In medicine a placebo is an inactive substance given to a patient which appears to bring benefit, but has no direct effect on a disease process. Its positive effect is psychological or non-specific (that is, there is no direct causal link between the treatment and the disease outcome). Let us briefly consider two scenarios: Susan S. has heard through the grapevine about a new dietary supplement that some people say helps MS. When she talked to her doctor, she learned that the supplement had been tested thoroughly and showed no actual benefit for the disease. Nonetheless, because some people claimed it worked for them, and because it was clearly safe and inexpensive, she gave it a try. For a short time, the dietary supplement actually helped her to feel better. John C. has been offered a place in a clinical trial for a new drug treatment for MS. His doctor has told him that the study will be a well designed, controlled and blinded experiment, and that John has a 50-50 chance of receiving the active drug or a "sham" treatment which is being tested for comparison. The rate of progression of John's MS slowed down briefly after he started the drug so that he was surprised when he later found out he was in the placebo group. What both John and Susan are experiencing, in different ways, are aspects of the placebo effect: it can help people feel "physically better" for a time it can be used to help a person with a disease like MS develop a positive mental attitude it can be a necessary component in the determination of a clinical trials efficacy it can confuse the evaluation of new therapies and complicate the design of clinical studies It is an intriguing phenomenon that has both admirers and critics and its roots go way back in history. The history of placebo in medicine Before the advent of twentieth century drugs that treat disease at the level of specific biological problems (for instance, Penicillin as an antibiotic to treat infection), the placebo effect was medicine's most potent weapon in its attack on disease. Crocodile dung, Lizard's blood, oil of earthworms, Goose and Sheep dung, burning Juice of Cassia and even the touch of a king are all examples of "medicines" used between 1500 B.C. and the nineteenth century. While not providing any actual therapy for any disease, the patient's and physician's perceptions that these treatments conferred benefit made them acceptable therapies, and such remedies were touted widely for centuries. Today, more sophisticated placebos have taken their place in the modern lore of therapeutic claims. The ingredient common to all of these treatments historical or current- is the belief that they are effective. Just why disorders seem to improve under such circumstances is key to our consideration of the placebo effect. How do placebos actually work? It is not known exactly what effect positive emotional states have on the biological conditions that underlie MS, but it is important to recognize that the placebo effect has a real biological basis. The act of taking a placebo can and does alter the functioning of the body: placebos have been shown to alter blood pressure and heart rate, influence GastroIntestinal secretions, change circulating Blood levels of Proteins and produce changes in Immune System function, the latter of which might be particularly important in MS. Most is known about how the placebo effect works biologically in alleviating pain. In pain, placebos, associated with the belief that one is receiving a pain-relieving drug, work because they serve to mobilize pain relieving peptides called Endorphins. Studies have shown that administration of the drug Nalaxone, which blocks the effects of pain relieving Endorphins, reverses the placebo effect, demonstrating that the production of Endorphins is directly related to the placebo relief of pain. While the pain analogy may not be directly related to what happens in MS placebo effects, it does point to a real biological effect that needs to be explored and understood better. Perhaps a more MS relevant area concerns Immune Responses to placebo experiences. Only a few attempts have been made to correlate psychological factors with immune function in MS: our studies at Albert Einstein found that psychological distress was associated with Immune changes in MS, but another more sensitive study we did produced results that were less clear. More indirect information comes from conditioning experiments classical psychological studies in which the body is "taught" to respond biologically to certain mental states. The historical roots of how behavioral and physiological responses can be conditioned derives from the work of Dr. Ivan Pavlov. Pavlov discovered that dogs can be trained to salivate to the sound of a bell. By repeatedly pairing the sound of a bell with the presentation of food, the dogs eventually learned to salivate- the biological response - in the absence of food, whenever the bell was sounded. Thus, the physiological response of salivation was conditioned to the sound of the bell. More recent research on conditioning shows that many biological responses can be changed through conditioning, such as Blood Pressure, Heart Rate, and even Immune Responses, as noted previously. The ability to condition Immune Responses in animals and perhaps in humans may have implications for understanding how placebo expectation - psychological phenomena - can affect disease. Conditioned suppression of Immune Responses has been shown since 1974, following a serendipitous discovery by a psychologist who was studying how quickly mice can learn to avoid drinking water which is flavored with something associated with Nausea - in this case, Nausea induced by the drug Cyclophosphamide (an Anti-Cancer agent, which by coincidence is sometimes used to try to arrest Progressive MS). Dr. Robert Ader, a psychologist at the University of Rochester, paired the taste of Saccharine-flavored water with an injection of of Nausea producing Cyciophosphamide. While Cyclophosphamide produces Nausea, it also is a potent short-term suppressor of Immune System function, which can be easily demonstrated by laboratory analysis of immune activity. Dr. Ader found to his surprise that, after a period of training, animals that had been conditioned with Saccharine and Cyclophosphamide over several test periods actually showed ImmunoSuppression even in the absence of the Cyclophosphamide treatment when given Saccharine alone. The animals had somehow "learned" to associate the flavored water with Immunosuppression which had resulted from drug delivery; over time, the drug delivery wasn't even needed ! In a related phenomenon, it has also been shown that people with severe hay fever can "learn" to react with bona fide symptoms of their allergies simply by being shown pictures of hayfields! A conditioned allergic response clearly is occurring, since the pictures themselves cannot have elicited the symptoms. Although the mechanisms for this type of conditioning are not understood, it is clear that life forms as simple as single-ceiled animals or as complex as human beings are capable of being conditioned. Perhaps the magic of the placebo effect can in part be explained by the body's responding biologically in conditioned fashion in the right set of circumstances. The placebo effect in MS clinical trials In any clinical experiment testing safety and efficacy of new treatments for MS, the placebo effect is likely to occur and can seriously compromize understanding of whether or not the new agent actually shows benefit. It is not uncommon for some patients in such trials to have an apparent positive response or "benefit" even if they are not receiving active treatment. Among the earliest well-designed clinical studies of MS in the 1960's examining the use of ACTH for speeding recovery of acute attacks of the disease - a significant percentage of patients being treated with an inactive control substance showed improvement which, to this day, has caused lingering doubts about the real effectiveness of this therapy. Many more recent clinical studies for the effectiveness of other agents in MS have shown that many patients show some level of improvements once they are enrolled in a study, independent of whether they are treated with active or sham therapy. A recent example is found in the controlled study of Copolymer-I for chronic progressive disease. In that study, a placebo effect was evident in that disease progression in untreated patients slowed upon their acceptance into the study, when compared with pre-study progression rates. In Multiple Sclerosis, the placebo effect is more problematic than with many other diseases, says Dr. Stephen Hauser, newly appointed chairman of Neurology at the University of California at San Francisco. "This makes it very difficult for a doctor to assess the patient's response to a drug unless the effect is truly overwhelming. So I think MS, more than any other disease I can think of, requires carefully controlled placebo trials." Only through such studies, where subjects on active treatment are compared with subjects treated with a sham therapy (and preferably, where neither group knows whether its therapy is active or not), can placebo effects be subtracted from true treatment benefit. Any good therapy must show benefit over the placebo. Origin of the placebo effect in clinical trials Dr. Sarah Minden, a psychiatrist at Harvard University and ABT Associates in Cambridge, Massachusetts, feels that some people respond to the placebo or sham treatment simply because they are convinced that they have been given the real treatment, and may even have a real physical reaction to the placebo. "In MS, a person might feel he is walking better, feeling stronger, have better vision. He feels he is responding to the drug. But he's getting something inert, so it must have something to do with his psychological expectations and hopes." Dr. Hauser agrees: "I think it stems from the psychological belief that you're being helped. Many things happen when people enter clinical trials. They become excited, hopeful and, in fact see their doctors more often. Family members may become more optimistic. All of these factors may influence their responses to the trial." Can the placebo effect be used to help? If conditioning or even random psychological events can contribute to a state of well being or even clinical and laboratory changes in animal experiments or in humans, is it possible to use the placebo effect for real therapeutic benefit? In 1974, Norman Cousins published a now-famous account of his recovery from a serious collagen illness in the New England Journal of Medicine. One of the interesting features of his reported recovery was the strong belief that positive emotions might help. Working with a trusted physician friend who assisted him in management of the medical aspects of his treatment, Mr. Cousins set about creating a positive emotional atmosphere around himself. His conclusion - supported by some biological data - was that periods of laughter were actually correlated with physical improvement. While there is no doubt that laughter alone cannot cure disease, such observations have led many to conclude that a positive mental attitude is a requirement in the day-today management of chronic or acute illness. Such hypotheses have led to significant growth in research correlating psychological factors with basic biological phenomena related to health and disease, and in particular to Immunology. Although reports by Cousins and others have generated public interest and stimulated new mind-body research, some have taken these findings to mean that a positive attitude can influence or even cure all disease. It is important for researchers, physicians and, above all, patients to approach this point of view with extreme caution. It can cause guilt and unnecessary distress because it induces the misconception that the individual with MS is responsible somehow for acquiring MS or for the progression of the disease. The fact is, it is not known if the mind or one's mental state can influence the underlying disease process in MS, or what the hypothesized mechanisms of this interaction would involve. It is known that MS happens to people with every conceivable mental state and personality type, and persons of all intellectual and socioeconomic levels. Similarly, it is not known why some people get more severe cases of MS than others, but severity of illness seems to be completely independent of psychological state. This caveat aside, the answer to the question, "Can the placebo effect be used to help?" Is "yes and no," because in fact the placebo response in the treatment of illness, and especially MS, remains shrouded in mystery. Some view it as a phenomenon that must be overcome in the evaluation of new therapies for efficacy and safety while others view it as a reservoir of hope, in that we may some day penetrate the mystery and gain a clearer understanding of the ways in which the mind may have an impact on illness. Probably both perspectives are appropriate and deserve continued attention. Although it is clear today that psycho-social and "placebo" factors play a role in how one adjusts to living with MS, it is just as clear that placebo effects are too short-lived and incomplete to provide meaningful treatment for a disease like MS. However, how psychological factors, placebo effects, may work in conjunction with new biologically targeted treatments is an open question. Perhaps present and future research will be able to gain more knowledge on the key questions: Does the mind influence MS; what is the nature and extent of the mind's influence; what are the mechanisms involved; and finally how can the mind be used in a truly comprehensive treatment plan for people with disease? Placebos Questions Often Asked Is it possible to self-induce a placebo effect? Placebo effects are always self-induced by the belief that one is taking a helpful remedy or procedure. Without this conviction, a placebo effect will not occur. The question sometimes is raised, however, "If you know that it is an ineffective medication, can it still help you?" It is difficult to see how someone could know that what he or she was taking was a placebo and still benefit from it. The knowledge that one is taking an ineffective treatment is incompatible with what is required to generate a placebo effect. What's the difference between a quack remedy and the placebo effect? Quack remedies and placebos both have something in common. There is no causal link between the "treatment" and the disease outcome. However, more deception is present with the administration of "quack" remedies, in that promises and claims of efficacy are made directly without scientific justification. When aphysician prescribes a placebo, it is anticipated that it will bring short-term relief to some condition for which there is no other established treatment. In clinical trials, placebos arc administered with the permission and knowledge of participants (even though no one knows which subjects received the placebo). The purpose of administering placebos is to obtain knowledge about treatment effectiveness in a scientific study. The purpose of administering a quack remedy is to deceive for profit. Since the placebo effect has a real biological impact, is there a way to extend the placebo effect? Placebo effects tend to be self-limiting. If a person with MS were taking a placebo and "felt better," then experienced an exacerbation, the belief that the placebo was helpful would be sorely challenged in most cases. Even if placebo effects were present, they would be difficult to sustain over time. Perhaps in the future we will learn to "manipulate" placebo effects so they can be helpful in MS. Also See: Placebo Response Dr. Frederick Foley, an associate professor of psychology at Yeshiva University, has been investigating the relationship among mental states, clinical symptoms, and the Immune System in MS for the last eight years. His studies have been based on both people with MS and mice with an MS-like disease (EAE). National Multiple Sclerosis Society 733 Third Avenue New York, NY 10017-3288 (212) 986-3240 INSIDE MS Spring 1993 Volume 10 No.2, p18