Parkinson's Disease Initial Treatment: The Long Running Debate

There is a long running, sometimes rather heated debate about whether levodopa/carbidopa (Sinemet) or a dopamine agonist such as pramipexole (Mirapex) and ropinirole (Requip) is the superior initial treatment in Parkinson's Disease (PD). Levodopa use is associated with a variety of motor complications as noted below. As well, there was concern in the past that levodopa would be "used up" after a certain total amount was taken and complications would worsen. Also, however, dopamine agonist therapy is not without problems, as these drugs have been associated with compulsive gambling, excessive daytime sleepiness and some other problematic adverse effects. Recent treatment guidelines have suggested the use of dopamine agonists as initial therapy. Long term comparative studies were lacking. And, it has never been clear that any treatment has a material effect on the long term course or progression of PD, in part due to the large variability of the course of PD in any individual patient. This has been debated since selegiline was studied in the 80s.

Some background:

In addition to hallmarks of PD per se, such tremor, rigidity and bradykinesia, patients with PD suffer from a number of treatment related phenomena as they progress. One is the "on-off" effect, wherein the patient has a sudden lapse of benefit of the medications. Treatment-emergent dyskinesias are also problematic, and tend to worsen with disease progression. These effects tend to be associated with treatment with levodopa much more than the dopamine agonists.

Recently released as an early release article in Archives of Neurology (suggesting the editors recognize the potential impact of the results), the paper by the CALM cohort investigators sheds some light on this conundrum. The study was an open label extension of a lengthy (four year) randomized controlled trial comparing levodopa to pramipexole, with results previously published. The investigators followed study participants for up to 2 years after exit from the CALM-PD trial (Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease). As an aside, I must note that I am always amused by the clever acronyms chosen for such large multicenter trials.

At any rate, the investigators defined a cohort of 222 patients and measured a variety of variables (301 patients were enrolled into, and 183 completed, the double blind trial). And, in the end, they found little difference between the 2 treatments. Activity of Daily Living measures were nearly identical. PD ratings scale scores were similar. The levodopa group had more motor complications such as dyskinesias. The pramipexole group reported more sleepiness and edema. So, there were differences in side effects, but not overall impact of PD on patient's lives.

Of note is that over 90% of patients in each group were taking levodopa at the end of the observation period, implying that most of the pramipexole patients had been started on levodopa after exiting the double-blind study. Thus, the pramipexole cohort largely did not continue on pramipexole as single therapy after the trial ended. Also, a significant limitation is that patients who did not enter the open label phase (26.2% of the double blind study patients) were older and had more severe PD. Their absence from this analysis may obscure or reduce differences between the two groups.

Nevertheless, this long term trial does suggest that the differences between these early PD treatments may be less than previously thought. As the authors note: "Over the long-term, there is no strong evidence favoring either of these initial treatment strategies over the other."