The Placebo Effect in Clinical Trials in Parkinson's Disease
by J. Stephen Fink, MD, PhD
A medication may have several effects on a patient. Some effects may be directly related to the medication's effect on the body's functioning or physiology (this is called the pharmacological effect of a medication). Another effect of a medication may not be linked directly to the medicine's pharmacological effect. This is called the placebo effect. A placebo effect can be observed when a pharmacologically inert (inactive) substance (usually in the form of a pill) is administered. What is the placebo effect? What does the placebo effect have to do with the process of developing new treatments or new medications in controlled clinical trials? What is the importance of the placebo effect to clinical trials in Parkinson's disease?
The word placebo comes from the Latin verb "placere," that means, "to please." Placebo is an inactive treatment. Placebo effect is the effect on a subject (usually beneficial) resulting from the administration of a placebo. When a patient receives any treatment (whether it is an active treatment or not) there may be a beneficial effect experienced by the patient because there is an expectation of benefit. Placebo effects can result simply from contact with doctors or other health care providers, even in the mere act of interviewing or examining a patient. There may also be beneficial effects of additional treatment or improved care provided during a clinical trial of a new medication.
In the context of a clinical trial of new medications, the term "placebo effect" sometimes refers to any improvement in symptoms experienced by the control group. In addition to expectation of benefit, other contributors to this improvement in patients' symptom scores may include the tendency for patients to enter trials when their symptoms are worse, and "bias" in the rater's scoring of patients' symptoms. The beneficial effect resulting from the act of receiving treatment may be quite powerful and long lasting. For example, in some studies of asthma and pain, there was improvement of 30-40% in subjects given inactive medications (placebo medication).
The beneficial effect of receiving any treatment is not limited to medications, as the expectation of benefit alone may lead to improvement in symptoms after surgical procedures as well. A well-known example of this phenomenon in medical literature is the improvement in angina pectoris (chest pain from cardiac disease) that accompanied a control surgical procedure which consisted only of anesthesia and cutting the skin.
The placebo effect can interfere with the assessment of whether a new medication or treatment has genuine benefit. Therefore, when new medications are tested, they are commonly compared to an inactive treatment or placebo. This type of clinical trial is a placebo- controlled trial. When neither the patient nor the examiner knows whether the patient is receiving active treatment or placebo, the trial is referred to as "double-blind." When the subjects are assigned to active treatment or placebo groups by chance, this is called a randomized trial. Randomized, double blind, placebo-controlled trials offer the most effective way to control for the placebo effect and have become the "gold-standard" in clinical trial design for assessing new drugs or other treatments. For a new medication or therapy to be considered effective, it must be shown to be better than a placebo in a double-blind, randomized, placebo-controlled trial (sometimes the comparison is made to another active treatment, instead of placebo). Sometimes therapies that are thought to be effective are no better than placebo when tested in this type of trial.
Long-lasting placebo effects have been reported in Parkinson's disease. In some medication trials in Parkinson's disease patients, improvement in motor scores of 20-30% in patients assigned to the placebo group has been observed for up to 6 months. Similarly, improvement and deterioration in Parkinson's disease patients have been observed after the introduction and discontinuation, respectively, of placebo medication. Placebo effects appear to be particularly evident in the clinical trials of surgical therapies.
In the double blind, clinical trial of human fetal transplantation in Parkinson's disease conducted by Fahn, Freed and colleagues, the control group received an "imitation" surgical procedure; several of the patients in the control group rated themselves improved one year later'. Similarly, 30% improvement in motor scores in the placebo (imitation surgery) control patients was observed in the double-blind trial of porcine mesencephalic tissue in Parkinson's patients. In this trial, improvement in the control group lasted at least 18 months, longer than had been previously observed in clinical trials of medications, suggesting that placebo effects may be more powerful in clinical trials of surgical therapies.
What causes the placebo effect? It is not possible to test adequately for placebo effects in laboratory experiments because animals are not known to have responses to placebo. It has been assumed that the placebo response is not mediated directly through a physical or chemical effect of treatment. However, a remarkable study by Jon Stoessl and colleagues demonstrated that the placebo effect in Parkinson's patients was accompanied by a release of brain dopamine from the remaining midbrain dopaminergic cells. This suggests that the improvement in motor function that is observed in the placebo groups of clinical trials in Parkinson's disease patients might be due, in part, to actual physiological changes in the damaged brain dopamine nerve cells.
In summary, the placebo effect is an important factor in the testing of new medications for Parkinson's disease. It dictates the design of clinical trials of new medications by the inclusion of placebo groups. The placebo effect might be considered to "benefit" those Parkinson's disease patients who join clinical trials and are assigned to the placebo group, as they may demonstrate improvement in symptoms. Indeed, some of this improvement in symptoms in the placebo group may actually be due to beneficial changes in brain dopaminergic nerve cells. This perspective underscores the often-spoken adage at Parkinson's disease centers: "One of the best things to do when a patient first learns of the diagnosis of Parkinson's disease is to join a clinical trial." Among the many benefits of such participation may be the placebo effect!
Dr. Fink was a practicing clinical neurologist, a researcher and Chairman of the Neurology Department at Boston University School of Medicine until his untimely death at a young age. He continues to be missed by his patients, his colleagues and the entire Parkinson's community.