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Why Research Supports the Practice (of a Placebo Effect)

Several investigators interviewed by Neurology Today said new research has identified brain mechanisms that enable the placebo effect to produce significant relief, especially for certain neurologically mediated disorders.

Nico J. Diederich, MD, and Christopher G. Goetz, MD, reported in an August paper in Neurology, for example, that “a positive placebo response is seen in up to 50 percent of patients with Parkinson disease [PD], pain syndromes and depression enrolled in placebo-controlled clinical trials.”

The effect was so strong that changes on PET of patients with PD who received a placebo were equal to changes in patients who received actual medication. The authors summarized evidence that the expectation of benefit produced improvement in parkinsonism through dopaminergic activation of the striatum, and through changes in cell firings of the subthalamic nucleus.

Dr. Goetz, director of the Movement Disorders Center at Rush University Medical Center in Chicago, also described evidence of placebo-associated improvement in PD in two 2008 articles in the journal Movement Disorders.

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DR. CHRISTOPHER C. GOETZ: “Weve seen placebo responses for both parkinsonism and for dyskinesia, which is a bit of a confound because if the placebo effect involved a simple neurochemical augmentation of dopamine, one would expect PD to get better, but that the dyskinesia, which is a hyperdopinergic behavior, might actually get worse. That did not occur.”

“We've seen placebo responses for both parkinsonism and for dyskinesia, which is a bit of a confound because if the placebo effect involved a simple neurochemical augmentation of dopamine, one would expect PD to get better, but that the dyskinesia, which is a hyperdopinergic behavior, might actually get worse,” Dr. Goetz said. “That did not occur. When the target behavior under study was parkinsonism, we found improvement in parkinsonism with placebo treatment. When the target behavior under study was dyskinesia, we found improvement in dyskinesia with placebo treatment. This dichotomy suggests there might be other nuclei or other neurochemcials involved in placebo-associated improvement.”

The data they summarized on placebo-mediated pain relief and its relationship to endogenous opioid release suggested that it is triggered primarily by activation of the rostral anterior cingulate cortex — a process that can be reversed by opioid antagonists.

The authors of a 2001 study in Science found that some PD patients who received a placebo displayed brain changes identical to those produced by levodopa, which boosts brain levels of dopamine.

“PD is a condition where you're supposed to lose most of your dopamine, and yet these people could release a substantial amount of dopamine,” said lead author A. Jon Stoessl, MD, professor of neurology and director of Pacific Parkinson's Research Centre at the University of British Columbia in Vancouver. “Based on PET, a substantial amount (of dopamine) is being released. It could be a 10-fold increase. It's equivalent to what you would see after giving a healthy person amphetamines.”

Like Dr. Goetz, Dr. Stoessl believes that the expectation of benefit plays a key role in the placebo effect, with PET and fMRI suggesting that this process is driven largely by the dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortices. While this may be related to dopamine release, Dr. Stoessl doesn't believe dopamine plays the primary role.

“It may have a permissive effect in that once you've activated reward circuitry, you've laid the foundation for getting better,” he said. “That may open the way for other disease-specific pathways.”

A review of articles about the placebo effect published online in June in advance of the November print edition of Brain echoes Dr. Stoessl's interpretation, observing that a patient's expectancy of improvement may influence outcomes as much as some active interventions. “Maximizing this expectancy effect is important for clinicians to optimize the health of their patient,” the article stated.

REFERENCES

• Diederich NJ, Goetz CG. The placebo treatments in neurosciences: New insights from clinical and neuroimaging studies. Neurology 2008;71:677–684.
    • Fuente-Fernández R, Ruth TJ, Stoessl AJ, et al. Expectation and dopamine release: Mechanism of the placebo effect in Parkinson's disease. Science 2001;293:1164–1166.
      • Goetz CG, Wuu J, Leurgan S, et al., for the Parkinson Study Group. Placebo response in Parkinson's disease: Comparisons among 11 trials covering medical and surgical interventions. Mov Dis 2008;23(5):690–699.
        • Goetz CG, Laska E, Russ H, et al. Placebo influences on dyskinesia in Parkinson's disease. Mov Dis 2008;23(5):700–707.
          • Lidstone SC, Stoessl AJ. Understanding the placebo effect: Contributions from neuroimaging. Mol Imaging Biol 2007;9(4):176–185.
            • Oken B. Placebo effects: clinical aspects and neurobiology. Brain 2008;131(11):2812–2823; E-pub 2008 June 21.