Caffeine: No Effect on Motor Symptoms in Parkinson's

October 03, 2017

Caffeine given at the dose equivalent of three cups of a coffee a day did not improve motor symptoms in patients with Parkinson’s disease in a new randomized controlled trial.

A previous, much smaller study suggested a benefit of caffeine given at rapidly increasing doses over a 6-week period, lead author, Ronald B. Postuma, MD, Montreal General Hospital, Montreal, Quebec, Canada, told Medscape Medical News.

"The current trial was two and half times larger and six times longer and didn't show an effect, so I think we can say from this that caffeine is not of any benefit as a symptomatic treatment for Parkinson's disease," he added.

Dr Postuma said the study, which was published online in Neurology on September 27, illustrates the problem of overenthusiastic publicizing of potential interventions that haven't been tested properly.

"Every other week there is another craze for something that is supposed to help Parkinson's disease, but none of them have worked out when tested in larger studies. These crazes make patients feel pressure to take the next big thing that might just work, but they are invariably false hopes," he stated.

Nevertheless, there is still a possibility that caffeine may protect in some way against the risk of developing Parkinson's, he said.  

Protective Effect?

Dr Postuma explained that the idea of testing caffeine as a treatment for Parkinson's came about from epidemiologic studies showing that people who don't drink coffee or other caffeinated drinks appear to have a higher risk for the disease, suggesting that caffeine may have a protective effect. 

In addition, caffeine is an adenosine antagonist, and adenosine receptors are closely coupled with dopamine receptors in the basal ganglia, he elaborated. Preclinical studies have shown that adenosine antagonists can act in a similar way to dopamine agonists, increasing dopamine transmission, which is the mainstay of Parkinson's treatment. Adenosine antagonists are now being investigated as potential drugs for the condition.

"Essentially, they could be the same as just very expensive coffee, so we thought it was worth trying caffeine itself," Dr Postuma said.

In the multicenter parallel-group controlled trial, patients with Parkinson's of 1 to 8 years' disease duration and  Hoehn and Yahr stages I to III who were receiving stable symptomatic therapy were randomly assigned to caffeine 200 mg twice daily (morning and lunchtime) vs matching placebo capsules for 6 to 18 months.

The trial was halted early — after enrollment of 121 patients — when an independent data monitoring committee agreed that it could not achieve its primary outcome. 

Results showed that over 6 months, scores on the Movement Disorder Society–sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS] III, the primary endpoint, worsened by a mean of 0.64 points in the placebo group, compared with 0.16 points in the caffeine group. This was a nonsignificant difference of –0.48 points (95% confidence interval, –3.21 to 2.25).

Removing protocol violations (including study medication termination) or stratifying to baseline caffeine use did not affect the results.

Secondary outcomes, motor signs, and motor symptoms (MDS-UPDRS-II) also did not change at any time point, and quality of life did not differ.

There was a slight improvement in somnolence over the first 6 months, which attenuated over time, but the caffeine group showed a slight increase in dyskinesia and slightly worse cognitive testing scores (average Montreal Cognitive Assessment score was 0.66 points worse than in the placebo group).

Noting that studies in the general population, including elderly persons, have generally found small improvements in cognition with caffeine,  the researchers say it is difficult to speculate on a plausible mechanism for their findings of worse cognitive function in the caffeine group. But they add that this was an exploratory finding, and, given multiple comparisons in the study, such findings may simply be chance.

Caffeine was well tolerated, with prevalence of side effects similar to that with placebo.

"The dose we chose for this study was equivalent to three cups of coffee a day and we didn’t really want to go higher than this as higher doses can cause side effects, such as nausea and shakes," Dr Postuma noted. "We could try again with double the dose, but I think it will be unlikely to work."

Not Treatment but Prevention?

In an accompanying comment, Charles B. Hall, PhD, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, says the study appears well run and not biased by differential adherence or loss to follow-up.   

"Although the small number of participants…resulted in a wide confidence interval and cannot exclude a small effect, this trial suggests that caffeine does not significantly improve Parkinson disease symptoms and that it should not be a priority for future Parkinson disease intervention studies," he adds.

Dr Postuma suggests that while this study seems to rule out caffeine as treatment for Parkinson's, it still might play a role in protecting against the condition, according to the epidemiologic data. Alternatively, though, low caffeine intake may just be a marker of the type of person who develops the condition. 

He explained that there appears to be something different about people destined to develop Parkinson's disease in terms of their reward mechanism. In addition to not drinking coffee or other caffeinated drinks, epidemiologic data show that patients with Parkinson's are less likely to smoke. 

"The general profile of people who develop Parkinson's is responsible, hardworking, loyal, non-risk-taking, nonimpulsive — exactly the type of people who wouldn't be addicted to caffeine or smoking," he said. "We know the dopaminergic system is involved in the reward feeling when good things happen, and we know dopaminergic transmission is affected in Parkinson's disease. It may be that more impulsive people who probably have a greater reward reaction have a greater dopamine reserve."

Commenting for Medscape Medical News, Alastair Noyce, PhD, University College London Institute of Neurology, United Kingdom, elaborated on this point.

"Much of the epidemiological literature is undertaken with risk of Parkinson's as the outcome," Dr Noyce said.

"First, it is important to note that the factors that affect progression may not be the same as those that affect risk, and secondly, whether we are talking about risk or progression, the current study was only really (at least at the first stage) designed to assess symptomatic benefit, not disease modification," he noted.

"For that reason, I think further work is required before one can rule out caffeine as a potential neuroprotective agent."  

The study was supported by Canadian Institute of Health Research, Webster Foundation, Fonds de Recherche du Québec-Santé. Dr Postuma reports he has received grant funding from the Canadian Institute of Health Research, Webster Foundation, and Fonds de Recherche du Québec-Santé for this study. Other coauthors have disclosed no relevant financial relationships.

Neurology. Published online September 27, 2017.  Abstract, Comment

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