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For Patients with Parkinson's Disease, Expensive Placebo Works Better

Sunday February 01, 2015

Robbie Gonzalez

io9 - In a recent study, an "expensive" salt solution was shown to to be significantly more effective at managing the symptoms of patients with Parkinson's disease than an "inexpensive" one. The salt solutions were identical placebos.

Scientific American's Karen Hopkins summarizes the study's design and findings:

To examine whether the perceived cost could be a factor, researchers told 12 people with Parkinson's that they would be receiving two formulations of a new medication. The patients believed that one version of the drug cost $100 a dose, while the other one cost 15 times as much.

The results? Participants who started with the supposedly high-priced drug showed 28 percent greater improvement in motor skills than those who got the cheaper placebo first.

The researchers – lead by Alberto J. Espay, an associate professor of neurology at the University of Cincinnati – reported their findings in this week's issue of the journal Neurology. "Expensive placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to, albeit less than, levodopa" the researchers write.

At The New York Times, Nicholas Bakalar adds that "the effect of the expensive placebo was not significantly different from that of levodopa, the most effective medication for Parkinson's disease." This observation says as much about the potency of the placebo affect as it does about the neurological mechanisms of Parkinson's disease, and, to a lesser extent, the inadequacies of levodopa. It's worth unpacking.

Levodopa, or L-DOPA, is the precursor to the neurotransmitter dopamine. Because Parkinson's disease is largely attributable to the insufficient formation of dopamine in the brain, L-DOPA has, for several decades, been the go-to drug for the treatment and management of Parkinson's symptoms. Neurologists call this a "dopamine replacement strategy."

It follows that the strength of the placebo effect in this particular instance could be due to the neural mechanisms of Parkinson's disease, itself. "One of the reasons why the effect is so large is that it's mediated by dopamine," Espay told The Times. "We make more dopamine when we have heightened expectations of efficacy."

Now, L-DOPA treatment is usually effective in the early stages of the disease, but can lead to complications over time. It's also wholly ineffective in modifying the course of the disease. In other words: L-DOPA may be one of the best treatments for Parkinson's Disease, but it leaves a lot to be desired, especially in the long term.

That said, the surprising role of heightened expectations of efficacy in the study should not be ignored. The placebo effect (and its biomedical foil, the nocebo effect) remains one of medicine's greatest enigmas, and seems to have become more mysterious – not to mention increasingly relevant – since the turn of the millennium. Steve Silberman writes extensively on the pharmaceutical industry's "placebo problem" in a 2009 issue of Wired:

The upshot is fewer new medicines available to ailing patients and more financial woes for the beleaguered pharmaceutical industry. Last November, a new type of gene therapy for Parkinson's disease, championed by the Michael J. Fox Foundation, was abruptly withdrawn from Phase II trials after unexpectedly tanking against placebo. A stem-cell startup called Osiris Therapeutics got a drubbing on Wall Street in March, when it suspended trials of its pill for Crohn's disease, an intestinal ailment, citing an "unusually high" response to placebo. Two days later, Eli Lilly broke off testing of a much-touted new drug for schizophrenia when volunteers showed double the expected level of placebo response.

It's not only trials of new drugs that are crossing the futility boundary. Some products that have been on the market for decades, like Prozac, are faltering in more recent follow-up tests. In many cases, these are the compounds that, in the late '90s, made Big Pharma more profitable than Big Oil. But if these same drugs were vetted now, the FDA might not approve some of them. Two comprehensive analyses of antidepressant trials have uncovered a dramatic increase in placebo response since the 1980s. One estimated that the so-called effect size (a measure of statistical significance) in placebo groups had nearly doubled over that time.

It's not that the old meds are getting weaker, drug developers say. It's as if the placebo effect is somehow getting stronger.

The fact that an increasing number of medications are unable to beat sugar pills has thrown the industry into crisis. The stakes could hardly be higher. In today's economy, the fate of a long-established company can hang on the outcome of a handful of tests.

Why are inert pills suddenly overwhelming promising new drugs and established medicines alike? The reasons are only just beginning to be understood. A network of independent researchers is doggedly uncovering the inner workings—and potential therapeutic applications—of the placebo effect. At the same time, drugmakers are realizing they need to fully understand the mechanisms behind it so they can design trials that differentiate more clearly between the beneficial effects of their products and the body's innate ability to heal itself. A special task force of the Foundation for the National Institutes of Health is seeking to stem the crisis by quietly undertaking one of the most ambitious data-sharing efforts in the history of the drug industry. After decades in the jungles of fringe science, the placebo effect has become the elephant in the boardroom.

Read the full placebo study in the latest issue of Neurology. Read the rest of Steve Silberman's feature on the placebo problem at Wired.



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