In this randomized controlled trial, we found no clear benefit of caffeine upon excessive daytime somnolence in PD, although there appeared to be a modest effect on per-protocol analysis. However, we found improvement in motor manifestations, with a 3.2-point improvement on the UPDRS part III, and 4.7-point improvement on the total UPDRS.
On analysis of the primary outcome, we found no significant benefit of caffeine on excessive somnolence. However, these results must be interpreted with caution. There was a 1.71-point improvement in the caffeine group that was statistically borderline on intention-to-treat, and significant on per-protocol analysis. The withdrawal/reduction of dopamine agonists by 2 placebo patients, with corresponding drops in ESS score (of 7 and 1 points), likely biased results substantially. Also, although the ESS has been validated in PD,22
and successfully used in previous clinical trials of somnolence in PD,13–15
it is possible that negative results could be due to limitations of the instrument. In particular the CGI-C, with somnolence as the target symptom, demonstrated significant (but small) improvement. Whereas the ESS only assesses episodes of actual sleep, the CGI-C is a global scale which can incorporate other sensations, e.g., fighting sleep and mental fogginess, which are important features of somnolence in PD. There is often poor correlation between subjective and objective measures of sleepiness in PD, and patients with PD may even be unaware of a daytime nap soon after it occurs.12,23
Therefore, objective measures, such as the maintenance of wakefulness or Multiple Sleep Latency Test, would have been of interest—however, in addition to adding participant burden, these tests have not been validated in PD, and may not reflect the somnolence experienced by patients in daily life. Regardless of statistical significance, the point estimate of difference in ESS remains small, so the clinical significance of any change is unclear.
This study has also found evidence that caffeine can improve motor manifestations of disease. Numerous lines of evidence have suggested potential beneficial effects of caffeine on PD. Caffeine's principal mechanism of action is antagonism of the adenosine-2A (A2A) receptor, which is involved in striatopallidal neuronal activity in the indirect pathway.4,24
Adenosine receptors are colocalized as heteromers with dopaminergic D2 receptors, inhibiting effects of dopaminergic transmission.25,26
Numerous animal studies have found motor improvement in toxin-induced models of PD,27
in dopamine-deficient mice,28
and in drug-induced parkinsonism29
with caffeine. Caffeine may also increase bioavailability and prolong the clinical effect of levodopa30
(note that the clinical effect of caffeine may persist even after levodopa levels decline, suggesting that the D2 receptor interactions are also important). Two early small-scale human studies evaluated caffeine as a potential symptomatic agent in PD, and found no effect.31,32
However, these were limited by very atypical dosing (e.g., 1,000 mg acute dose), or a single assessment in time. A recent study documented improvement in gait akinesia with 100 mg caffeine daily in patients with PD with gait freezing.3
Very recently, we found a UPDRS reduction with caffeine in an open-label dose escalation pilot study using similar doses to the current trial.2
Of note, there is increasing interest in the role of newer A2A antagonists for treatment of motor PD. Recent trials of istradefylline and preladenant have demonstrated modest (1–1.2 hour) reductions in off time, and modest (1.1 to 3.2 points) improvements in UPDRS part III.6,7,33,34
Although methodologic and patient population differences preclude direct comparison to our results, the effects of these newer antagonists upon UPDRS appear to be broadly similar to what we found with caffeine. Given caffeine's dramatically lower cost and well-established long-term safety profile, the advantage of the newer A2A antagonists relative to caffeine remains to be established.
In epidemiologic studies, there is compelling evidence that caffeine nonuse is associated with PD. Relative risks in large cohort studies range from 0.45 to 0.89,35
and a meta-analysis suggested a relative PD risk of 0.72 (95% CI 0.62, 0.84) for coffee intake vs no coffee intake.1
This inverse correlation is also present with tea and is not present with decaffeinated coffee, suggesting that caffeine itself is responsible.36,37
However, despite extensive documentation of this relationship between caffeine and PD, we lacked basic information to interpret these findings, mainly because we did not understand the effects of caffeine in PD. Although a true neuroprotective benefit is an important potential explanation, our findings suggest that other possibilities may also explain this relationship. The absence of a clear effect of caffeine on somnolence could suggest that reverse causality is important—patients in prodromal PD stages could lose the beneficial effects of caffeine upon alertness and wakefulness, and so spontaneously stop taking caffeine. Prospective epidemiologic studies (in which intake is assessed years before PD onset) argue against this, but depend upon assumptions of a relatively short prodromal phase of PD (i.e., <15–20 years). Second, caffeine's effect on motor manifestations suggests that symptomatic benefit could partially explain the epidemiologic findings; caffeine might delay onset of motor symptoms, resulting in an apparent protective effect. It is unclear if the modest symptomatic benefit we found would be of sufficient amplitude to produce such robust epidemiologic findings—studies of UPDRS progression in early PD suggest that a 5-point total UPDRS reduction would only delay diagnosis by approximately 6 months.38
Given that PD lasts a decade or more, this would presumably not translate to a 30%–40% reduction in prevalence. Note, also, that symptomatic and neuroprotective effects may not be mutually exclusive; some have suggested that early symptomatic treatment, by preventing maladaptive compensatory mechanisms in striatal structures, could also be neuroprotective.39
Some limitations of this study should be noted. The motor and quality of life benefits were secondary outcomes of the study, and therefore should be viewed as exploratory. Also, for these outcomes, selection of subjects with daytime sleepiness may have produced results not representative of other patients with PD. The study was not designed or powered to examine caffeine's effects upon fluctuations or dyskinesia, as only a subset of our patients had these features at baseline. A total of 15/61 patients in this study were originally enrolled into a crossover study and the first phase of their study is included; however, all trial procedures in the first phase were exactly the same as the parallel group study, so reliability should not be affected by their inclusion. To enhance generalizability and recruitment, we did not demand that all patients have no baseline caffeine intake—it is possible that some changed habitual caffeine intake during the 6-week study without notifying investigators. With a 2 ± 1 hour window during which patients were examined after caffeine intake, there was some variability in assessment time of UPDRS part III relative to caffeine. Although patients did not guess treatment allocation significantly better than chance, the point estimate exceeded 50%. It appears that any possible unblinding did not seem to be related to capsule appearance, taste changes, or adverse events; patients who guessed correctly generally did so because they recognized clinical benefits or lack of them. We did not ask investigators to guess treatment allocation, so cannot rule out unrecognized investigator unblinding. Importantly, the duration of the study was short—given caffeine's tachyphylactic properties (at least for somnolence), effects may lessen over the long term. Therefore, our findings must be confirmed in separate longer-term trials explicitly designed to assess effects in early disease, and in patients with fluctuations.