Placebo effect of medication cost in Parkinson disease: a randomized double-blind study

Abstract

Objective: To examine the effect of cost, a traditionally "inactive" trait of intervention, as contributor to the response to therapeutic interventions.

Methods: We conducted a prospective double-blind study in 12 patients with moderate to severe Parkinson disease and motor fluctuations (mean age 62.4 ± 7.9 years; mean disease duration 11 ± 6 years) who were randomized to a "cheap" or "expensive" subcutaneous "novel injectable dopamine agonist" placebo (normal saline). Patients were crossed over to the alternate arm approximately 4 hours later. Blinded motor assessments in the "practically defined off" state, before and after each intervention, included the Unified Parkinson's Disease Rating Scale motor subscale, the Purdue Pegboard Test, and a tapping task. Measurements of brain activity were performed using a feedback-based visual-motor associative learning functional MRI task. Order effect was examined using stratified analysis.

Results: Although both placebos improved motor function, benefit was greater when patients were randomized first to expensive placebo, with a magnitude halfway between that of cheap placebo and levodopa. Brain activation was greater upon first-given cheap but not upon first-given expensive placebo or by levodopa. Regardless of order of administration, only cheap placebo increased activation in the left lateral sensorimotor cortex and other regions.

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

Classification of evidence: This study provides Class III evidence that perception of cost is capable of influencing motor function and brain activation in Parkinson disease.

Figure 1. CONSORT flow diagram

At visit 1, subjects underwent an off-on motor assessment to determine their baseline magnitude of dopaminergic benefit. At visit 2, subjects in the practically defined off state were randomized to receive the cheap or expensive injectable dopamine agonist and crossed over in approximately 4 hours. CONSORT = Consolidated Standards of Reporting Trials.

Figure 2. UPDRS-III changes when expensive placebo was administered first

The expensive placebo group yielded the strongest reduction in UPDRS-III score, by 28% (A, p = 0.007), a magnitude of change not significantly different from levodopa (B, p = 0.14). The average change of cheap placebo, a 13% reduction in UPDRS-III score compared with baseline, was significantly less than levodopa (C, p = 0.042) and of lower magnitude than the change attained with expensive placebo (D, p = 0.034). Vertical error bars indicate SD. UPDRS-III = Unified Parkinson's Disease Rating Scale, Part III.

Figure 3. Effect of levodopa

Compared with baseline, there was a reduction of activity during task performance in selected brain regions, including the left putamen, left sensorimotor cortices, and left premotor cortex (voxel-wise p < 0.005, cluster of ≥37 voxels).

Figure 4. Effect of cheap vs expensive placebo stratified by order of administration, and interaction of cost by order of administration in the left putamen

(A) Compared with expensive placebo, cheap placebo produced stronger brain activation when given first. The magnitude of activation of expensive placebo was robust only when given after cheap placebo. Areas in red-orange show significant interaction of cost by order of administration, in a pattern similar to that shown in the supplementary material (see table e-2). (B) First administration greatly increased brain activation by cheap but not by expensive placebo. The effect of the second administration was confounded by the outcomes of the first administration. Task-induced brain activation (raw units) was greatest when cheap placebo was given first, with little change in activation when expensive was received after cheap (carryover effect). Activation was lowest when expensive placebo was given first, and the reduction was present but attenuated when cheap was received after expensive. We observed a qualitatively similar clinical response pattern shown by the directionality of the Clinical Global Impression (CGI) scores (improvement rated from 4 = unchanged to 1 = marked improvement), which are overlapped in red bars.