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Add Price to the Factors that Shape the Placebo Effect, New Study Suggests

Fitzgerald, Susan

doi: 10.1097/01.NT.0000461307.26400.a3
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In a novel trial design, Parkinson's disease patients were given placebos but were told they were either an expensive or cheap version of the same dopamine agonist. Those who were told they were taking a more expensive drug seemed to have better motor outcomes than those who thought they were given the cheaper drug.

Parkinson's disease (PD) patients responded better when given an “expensive” placebo compared with a “cheap” one, showing improvements in motor function approaching what was achieved with levodopa, according to a small study published in the Jan. 28 online edition of Neurology that highlights another twist to what is known about the placebo effect.

The 12 PD patients in the study were not aware they were getting placebo injections, but rather were told that they would be given two versions of the same dopamine agonist, identical except for manufacturing cost — $100 per dose for one drug and $1,500 for the other. The participants showed better motor function on standardized tests with the “expensive” placebo than with the cheap one, particularly when they received the expensive one first. Brain scans also suggested that participants responded more to the pricey placebo.

“‘Expensive’ placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to, albeit less than, levodopa,” the study concluded. “Perceptions of cost are capable of altering the placebo response in clinical studies.”

Previous studies have documented the significant role of the placebo effect in PD treatment. This latest study underscores “that there is a lot more than meets the eye in terms of the response patients have to different interventions,” lead author Alberto J. Espay, MD, FAAN, an associate professor of neurology at the University of Cincinnati, told Neurology Today. “While we want to believe that the benefits of a medication are simply due to the pharmacologic intervention, there are clearly a number of factors that affect the response to therapy.”

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Since the experiment involved deceiving participants — something that is usually considered unethical in medicine — it underwent an extensive internal ethics review before being approved.

The 12 participants were randomly assigned to receive either a supposedly expensive version of “novel injectable dopamine agonist” followed by a “cheap” version of the same drug, or the cheap version followed by the expensive one. The patients had moderate-to-severe PD and all had undergone “on-off” baseline testing to determine the magnitude of their response to levodopa.

Outcome measures for the study included the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale, the Purdue pegboard test, and a tapping task. Brain activity was measured using a feedback-based visual-motor associative learning functional magnetic resonance imaging (MRI) task.

Both placebos improved motor function, but the so-described expensive placebo “improved motor function two-fold over ‘cheap’ placebo if given first,” the researchers said. In addition, the data showed that “brain activation of visual-motor associative circuits is greatest when the ‘cheap’ placebo is given first and lowest when ‘expensive’ placebo is given first, suggesting greater brain ‘effort’ (more activity) under placebo conditions of lowered expectations.”

The researchers acknowledged that their study had limitations, including its small size and the fact that investigators who assessed patient response were aware of the premise of the study, though not about the order in which any given patient received the two placebo injections. Dr. Espay said it was notable that the so-called expensive injection was “almost as good as levodopa.”

“The expensive placebo group experienced a 28 percent improvement in motor function, as measured by the motor subscale of the UPDRS, a magnitude of change that was not statistically significantly different than levodopa,” Dr. Espay said. “The mean improvement after cheap placebo was 13 percent, which was significantly less than levodopa and statistically of lower magnitude than the change attained with expensive placebo.”

The precise mechanism for the placebo effect in PD therapy is not fully understood, Dr. Espay noted, though researchers suspect that the mere expectation of a benefit (reward) may enhance the production of dopamine in the brain.

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An editorial accompanying the study in the Jan. 28 edition of Neurology compared the price-driven placebo effect to what occurs with shoppers who are drawn to high-ticket designer items.

“For shoppers of luxury goods, satisfaction with a purchase might be proportionate to its expense,” wrote Peter A. LeWitt, MD, a professor of neurology at Wayne State University, and Scott Kim, MD, PhD, a senior investigator in the department of bioethics at the National Institutes of Health. They suggested that the study's conclusion that “price does matter” may turn out to be “bad news for health care providers committed to cost control, especially if such a mindset assumes better results should arise from more expensive drugs.”

James L. Bernat, MD, FAAN, the Louis and Ruth Frank professor of neuroscience and professor of neurology and medicine at Dartmouth College, told Neurology Today that this latest study is in line with previous studies that suggest that any number of non-pharmacologic factors are involved in the placebo effect. Many patients assume that brand name drugs work better than generics or that an injectable drug is more potent than a pill. A once-a-day dose may be perceived as packing more punch than multiple doses, and the words “new” or “novel” may imply superiority. The placebo effect isn't limited to drug therapy. Even surgery involves a degree of placebo effect, Dr. Bernat said.

“The placebo effect is not a magical thing,” he said. “It is a real physiologic response.”

With pain medication, for instance, the expectation of a benefit, or reward, can lead to the production of endorphins, Dr. Bernat said. The placebo effect is also a factor in improvement after treatment with antidepressant medications.

“The placebo effect seems to be related to patient expectations; the more powerful the expectation, the greater the placebo effect,” Dr. Bernat said. “That's why it is important to test new drugs against placebo.”

Dr. Bernat said one of the most important factors in the placebo effect is the strength of the doctor-patient relationship. If a patient trusts the doctor, then the patient may respond better to treatment.

How the factor of cost (expensive versus cheap) could be harnessed to enhance the placebo effect in real clinical practice is not clear, Dr. Bernat said. It's unlikely doctors will switch back to prescribing only higher-priced, brand-name drugs instead of generic ones simply to boost their patient's expectations of a benefit. In addition, the experiment in the study involved deceiving patients (who thought they were getting two identical versions of a dopamine agonist); the editorial that accompanied the study noted that “the ethical stakes in this study directly impinge on trust that is vital for the physician-patient relationship.”

Christopher G. Goetz, MD, FAAN, a professor of neurological sciences and pharmacology at Rush University, said the magnitude of the placebo effect is known to be strong with PD therapy.

In this latest study, Dr. Goetz said the role of drug cost in the placebo effect may be a “cultural reflection more important in North America than elsewhere.” In European countries with universal health care, cost may not be on a patient's mind. In the US, where price is a much-discussed aspect of health care, a patient might assume “it's expensive and therefore it must be better,” said Dr. Goetz, who is director of the Parkinson's Disease and Movement Disorders program at Rush University Medical Center.

He said that while the study clearly documented more clinical improvement in patients getting the expensive drug compared to the cheap one, it was more difficult to interpret the significance of the MRI component of the study.

Nico Diederich, MD, a professor of neurology at Centre Hospitalier de Luxembourg and University of Cologne in Germany, said the results from the latest study need to be interpreted with caution. He noted, for instance, that “the authors failed to analyze the neuropsychological profile of the participants.

“Are they in general risk-takers? Why did they subscribe to this study? Personality characteristics may well explain part of the effect and we should be cautious about generalization,” Dr. Diederich told Neurology Today in an email. Also, “announcing that one drug is cheaper may induce a ‘nocebo’ effect for this substance, thus enhancing the difference” between the two placebos.

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•. Espay AJ, Morris MM, Eliassen JC, et al. Placebo effect of medication cost in Parkinson disease: A randomized, double-blind study. Neurology 2015: Epub 2015 Jan. 28.
    •. LeWitt PA, Kim S. The pharmacodynamics of placebo: Expectation effects of a price as a proxy for efficacy. Neurology 2015; Epub 2015 Jan. 28.
      •. Neurology Today archive on the placebo effect:
        © 2015 American Academy of Neurology