Correspondence

Ropinirole as Compared with Levodopa in Parkinson's Disease

N Engl J Med 2000; 343:884-885September 21, 2000

Article

To the Editor:

Rascol et al. (May 18 issue)1 summarize the results of their study by stating that Parkinson's disease is best managed with ropinirole alone as the initial treatment, with levodopa used as a supplemental, second step if necessary. This recommendation is based on their finding that the risk of dyskinesias (medication-induced chorea) is lower with ropinirole.

If a reduced risk of dyskinesia is to be the basis for making a recommendation with such broad implications, then the magnitude of the problem must warrant this concern. We reviewed the medical records of 350 randomly chosen patients with Parkinson's disease who were seen in the past year at our clinic, all of whom were receiving carbidopa–levodopa as primary treatment. Eighty-three of the patients (24 percent) had dyskinesias rated as moderate or severe (a score of 2 or higher on items 32 and 33 of the Unified Parkinson's Disease Rating Scale [UPDRS]). Of the patients who had been treated for 5 years or less, only 7 percent had clinically significant dyskinesias, and of the 246 patients who had been treated for up to 10 years, only 12 percent had clinically significant dyskinesias.

One possible reason our findings differ substantially from those reported by Rascol et al. is that they defined “disabling” dyskinesia as a score of 1 or higher on UPDRS items 32 and 33. Thus, they included dyskinesia that occurred as infrequently as during 1 to 25 percent of waking hours each day and involuntary movements rated as “mildly disabling.” Many patients with dyskinesias do not find them particularly troublesome, with the movements being more of an embarrassment to family members and even their physicians.

Recent work by Hutton et al.2 shows that in most patients, Parkinson's disease can be managed well with levodopa therapy, without the use of adjunctive agonist therapy, over a five-year period. Our experience suggests that the risk of dyskinesias is a weak basis for a treatment recommendation with such broad clinical and financial implications. Although early use of an agonist makes sense in patients with early-onset Parkinson's disease, for patients in their 60s, 70s, or 80s, carbidopa–levodopa remains the best treatment.

Bradley C. Hiner, M.D.
Mahala Earnhart, R.N.
Marshfield Clinic, Marshfield, WI 54449

2 References

1
Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the in-cidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N Engl J Med 2000;342:1484-1491
Full Text | Web of Science | Medline

2
Hutton JT, Tolosa ES, Capildeo R, Morris JL. Levodopa-treated Parkinson disease has better long-term outcome than previously predicted. Arch Neurol 2000;57:758-759
CrossRef | Web of Science | Medline

To the Editor:

We care for many patients with Parkinson's disease who are more concerned with hypokinesia than with dyskinesia of a tolerable degree. The most difficult adverse event is hallucination rather than dyskinesia. So Rascol et al. could have drawn the opposite conclusion: early Parkinson's disease can be managed successfully, with a reduced risk of hallucinations, with levodopa alone. Although the authors state that hallucinations were mild and easily managed in most of their patients, the same might have been true of dyskinesia.

Toru Yamamoto, M.D.
Osaka Saiseikai Nakatsu Hospital, Osaka 531-0012, Japan

To the Editor:

In the study by Rascol et al., it is not surprising that the patients treated with levodopa had more dyskinesias than those treated with ropinirole, since levodopa is a stronger dopaminergic agent. Neurologists would like to know whether treatment with levodopa increases the susceptibility to the development of dyskinesias in patients with Parkinson's disease. This question could have been answered by administering an intravenous infusion of a dopaminergic stimulus as a challenge in the patients in the trial who were treated with levodopa or ropinirole monotherapy and quantifying the severity of dyskinesias.

The authors state, “There were no reports of falling asleep suddenly in either treatment group.” Does this mean that there were no such events? Were the patients questioned specifically about episodes of suddenly falling asleep? Such episodes have been reported in patients treated with pramipexole.1 A letter sent by SmithKline Beecham Pharmaceuticals to European physicians in November 1999 reported episodes of sudden sleep in 16 patients treated with ropinirole. This issue merits further discussion, especially given the authors' conclusion that “Parkinson's disease can be successfully managed for up to five years with ropinirole.”

Steven Frucht, M.D.
College of Physicians and Surgeons of Columbia University, New York, NY 10032

1 References

1
Frucht S, Rogers JD, Greene PE, Gordon MF, Fahn S. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999;52:1908-1910
Web of Science | Medline

To the Editor:

. . . Rascol et al. did not address the central issue of the importance of the dyskinesias. They demonstrated that the incidence of dyskinesias was lower with the use of ropinirole than with the use of levodopa. However, they dismissed the finding that the motor score on the UPDRS was significantly better with the use of levodopa. The main issue in the controversy over treatment is whether the lower incidence of dyskinesias with ropinirole is worth the smaller improvement in motor symptoms. Patients with Parkinson's disease are often unaware of early dyskinesias, and they may prefer dyskinesias to parkinsonian symptoms. It remains unclear whether early dyskinesias lead to more severe and disabling problems later in the course of disease. No assessments of the quality of life were reported. Like all good studies, this one raises more questions than it answers.

William J. Weiner, M.D.
University of Miami School of Medicine, Miami, FL 33136

Stewart A. Factor, D.O.
Albany Medical Center, Albany, NY 12303

Author/Editor Response

Dr. Rascol replies:

To the Editor: Several issues in these letters concern the importance of dyskinesia, its effect on the quality of life, the comparability of treatment efficacy, hallucinations, and sleep. An ongoing five-year extension of the present study incorporates tools for assessing the quality of life that were not initially available. We urge caution in comparing dyskinesia in different clinical trials and personal experiences, because without standardized tools, assessment methods are subjective. Dyskinesia becomes more severe and debilitating with time. Short of invasive treatments such as functional surgery, dyskinesias are largely irreversible. It is therefore crucial to delay their onset.

We regard as unfounded the opinion that the patients who received ropinirole were undertreated. There is some separation in UPDRS motor scores between the groups, but we believe this difference is clinically irrelevant. It is small and out of proportion to the difference in the risk of the development of dyskinesia (which was three times as great with levodopa as with ropinirole). Patients could have received more supplementary levodopa if they had wished or needed to receive more. Similar proportions of patients in the two groups completed the study or withdrew because of a lack of treatment efficacy. Our findings and other data1 suggest that the small although statistically significant difference in UPDRS motor scores may not accurately reflect what patients and prescribers expect from treatment.

It is suggested that hallucinations may be more important than dyskinesia. Hallucinations are usually more rapidly reversible and less frequent than dyskinesia. In our study, hallucinations were generally managed easily, and they rarely resulted in withdrawal from the study. We therefore consider it appropriate to regard dyskinesia as the prime factor on which to base our conclusion. The opposite conclusion may apply to treatment in older patients, who are at higher risk for hallucinations and at lower risk for dyskinesia.2

Episodes of suddenly falling asleep had not been identified when our study was designed, so the patients were not questioned about this problem. Such episodes may occur with all effective dopaminergic therapies, including all agonists3 and levodopa monotherapy.4 Epidemiologic studies rather than isolated case reports are required to establish the true incidence of these episodes and precipitating factors.

We recognize the efficacy of levodopa in controlling parkinsonian symptoms. However, in our proof-of-principle study, we show that there is an alternative strategy: initiating therapy with ropinirole, adding levodopa only as a second step, and thus reducing the risk of dyskinesia.

Olivier Rascol, M.D., Ph.D.
University Hospital, 31073 Toulouse CEDEX, France

for the 056 Study Group

4 References

1
Shoulson I. Pramipexole versus levodopa in early Parkinson's disease: the randomized controlled CALM-PD trial. Mov Disord 2000;15:Suppl 3:4-4 abstract.

2
Korczyn AD, Keens J, Oldham M, Macrae S. The safety and efficacy of ropinirole as early therapy in elderly patients with Parkinson's disease. Neurology 2000;54:Suppl 3:90-90 abstract.
Web of Science | Medline

3
Ferreira JJ, Galitzky M, Montastruc JL, Rascol O. Sleep attacks and Parkinson's disease treatment. Lancet 2000;355:1333-1334
CrossRef | Web of Science | Medline

4
Ferreira JJ, Galitzky M, Brefel-Courbon C, et al. “Sleep attacks“ as an adverse drug reaction of levodopa monotherapy. Mov Disord 2000;15:Suppl 3:129-129 abstract.

Citing Articles (1)

Citing Articles

1
Mariese A. Hely, John G.L. Morris, Wayne G.J. Reid, Robert Trafficante. (2005) Sydney multicenter study of Parkinson's disease: Non-L-dopa-responsive problems dominate at 15 years. Movement Disorders 20:2, 190-199
CrossRef