July 12, 2012 (Dublin, Ireland) — A new randomized trial shows improvements in objective motor measures with caffeine treatment over placebo in patients with Parkinson's disease (PD).

The improvements were significant despite treatment having only an "equivocal borderline improvement" in the study's primary endpoint of change in excessive daytime somnolence in these patients, investigators say.

"What was most interesting, I think, is we found that there was a motor benefit on the Parkinson's disease, so that this is a potential treatment for Parkinson's," first author Ron B. Postuma, MD, from Montreal General Hospital, McGill University, Montreal, Quebec, told Medscape Medical News.

"It was a modest improvement, but it was certainly there," he added, amounting to an approximately 5-point improvement on the Unified Parkinson's Disease Rating Scale (UPDRS).

The study was short-term, however. "What we need to do is see if we can see this effect in the longer term, because if we do, we have a new agent for Parkinson's disease, essentially," Dr. Postuma said.

These findings were presented here at the Movement Disorder Society's 16th International Congress of Parkinson's Disease and Movement Disorders.

Epidemiologic Evidence

Previous evidence from epidemiologic studies has consistently shown that caffeine, which acts as an adenosine 2A antagonist, is associated with a lower risk of Parkinson's disease, the authors write.

"We've been very intrigued by the fact that there's a relation between non-use of caffeine and Parkinson's disease," Dr. Postuma said. It's possible that caffeine is protective against the disease, but it's also possible, alternatively, that in those with Parkinson's, caffeine is not tolerated, it does not work for somnolence, or perhaps that caffeine is actually treating symptoms of the disease.

In this study, the primary outcome of interest was change in daytime somnolence as measured on the Epworth Sleepiness Scale, but researchers also looked at a variety of secondary endpoints, including motor severity, sleep markers, fatigue, depression, and quality of life.

A total of 61 PD patients with excessive daytime somnolence, defined as an Epworth Scale score greater than 10, were randomly assigned to receive 200 mg twice daily of caffeine or placebo. Effects then were analyzed by Bayesian hierarchical models, adjusting for study site, baseline scores, age, and sex.

"There was some clear improvement in their somnolence, it just didn't reach statistical significance," Dr. Postuma said. "Basically, there were a few protocol violations, which prevented a positive effect, but at any rate, the somnolence effect was modest."

"What was most interesting, I think, is we found that there was a motor benefit on the Parkinson's disease," he added.

The primary endpoint showed a nonsignificant reduction in the Epworth Scale with caffeine, the primary endpoint, but there was improvement on the Clinical Global Impression-Change, and a significant reduction in somnolence in the per-protocol analysis.

However, treatment with caffeine was associated with a significant change on the UPDRS and the objective UPDRS motor component.

Table. Change in Primary and Secondary Endpoints With Caffeine vs Placebo in PD

Endpoint Change, points 95% Confidence Interval
Change in Epworth (ITT) — primary endpoint -1.71 -3.57 to 0.13
Somnolence on Clinical Global Impression-Change (ITT) +64 0.16 to 1.13
Change in Epworth (per protocol) -1.97 -3.87 to -0.05
Change in UPDRS 4.69 7.7 to 1.6
Change in UPDRS (motor component) 3.15 5.50 to 0.83

ITT = intention-to-treat.

Other than some "modest" improvement in global health measures, there was no change in quality of life, measures of depression, or sleep quality, the authors note. Adverse event frequency was also similar between groups.

Caffeine is often associated with some irritability, anxiety, or difficulty sleeping, Dr. Postuma noted, "but we really didn't find that was the case in our study. We found it was very, very well tolerated." However, investigators did give caffeine doses in the morning and at lunch. "Obviously, if you take it in the evening, it's going to impact upon your sleep."

The potential motor benefits suggest that a larger long-term trial of caffeine is warranted, the authors conclude.

Currently, a number of other adenosine A antagonists are in clinical trials as treatments for Parkinson's disease, Dr. Postuma noted, "but these are going to cost thousands of dollars a year of course, while caffeine is going to cost pennies."

Significant Step

Lawrence Elmer, MD, PhD, professor in the Department of Neurology, and director of the Parkinson's Disease and Movement Disorders Program at the University of Toledo College of Medicine, Ohio, said the significant improvement seen in UPDRS scores in this study suggests the possibility that caffeine improves motor performance in Parkinson's, or possibly augments the effects of current therapies.

"As a number of adenosine 2a antagonists are in clinical trials, this result may not be that unexpected, but the authors' suggestion that a larger study of this potential treatment certainly seems warranted," Dr. Elmer told Medscape Medical News. "It would be a nice surprise indeed if one potential therapy for PD turned out to simply be several servings of espresso daily."

In a press statement from the society, Professor K. Ray Chaudhuri, MD, from Kings College Hospital, London, United Kingdom, calls the findings "a significant step forward in establishing [an] evidence base for treatment of nonmotor symptoms and excessive daytime somnolence in Parkinson's."

"The study is well performed, and although the primary outcome measure of Epworth [Sleepiness Scale] is not significantly altered, there is an emerging signal of improving somnolence on Clinical Global Impression with additional improvements in motor state," Professor Chaudhuri writes. "In clinical practice, this translates to experience of beneficial effect of caffeine in patients with excessive daytime somnolence."

This "highly needed" study should pave the way for a large-scale, multicenter, international study addressing the effect of caffeine in the treatment of excessive daytime sleepiness and related complaints in Parkinson's, he concludes.

Dr. Postuma has disclosed no relevant financial relationships. Dr. Elmer has received honoraria or payments for consulting, advisory services, speaking services, or unrestricted educational grants over the past 12 months from Lundbeck, Teva Neuroscience, UCB Inc, Impax Laboratories, and Novartis Pharmaceuticals.

Movement Disorder Society’s 16th International Congress of Parkinson's Disease and Movement Disorders. Abstract 421. Presented June 18, 2012.