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This report from the Sixth International Congress of Parkinson's Disease and Movement Disorders summarizes current research and the continuing debate on PD meds -- when to start levodopa, which meds to start with, comparisons between the various dopamine agonists, old and new agonists, etc. Once again no consensus yet among the experts. (full report available on Medscape at http://www.medscape.com) I think the last paragraph may be the most significant part of this report -- so I moved it to the beginning: "Perhaps the most relevant comment, sobering as it was, was made by Dr. Lees at the end of the discussion. He pointed out that when considering the entire course of PD, which can span several decades, the first 5 years are usually marked by relatively minor symptoms that can be controlled adequately with either levodopa or an agonist. As he put it, "the first 5 years are easy" in terms of treatment choices. The much more difficult period is the following years, during which motor fluctuations, variation in response to levodopa, and the progression of symptoms refractory to levodopa take a more serious toll on the quality of life of patients with PD than in the first 5 years. Thus, without denying the importance of making the best use of the treatment options that we have for the initial period, he expressed hope that the search will continue for better treatments for the more advanced stages of PD." FROM: Medscape Neurology, 2000 www.medscape.com Conference Highlights From the Sixth International Congress of Parkinson's Disease and Movement Disorders Clinical Trials in PD Long-term treatment of patients with PD with levodopa is accompanied, after a few years, by the apparently inevitable development of motor complications. These mostly consist of the following: 1. a shortened duration of efficacy (down to as little as 1 to 2 hours), which leads to "on-off" fluctuations in a patient's motor function; and 2. dyskinesias, which are continuous involuntary writhing movements of the face, neck, or limbs. Whether delaying treatment with levodopa helps to delay or reduce the severity of these complications remains an unanswered question, leading to difficult choices for most patients with PD and their physicians. Most patients would be willing to forgo use of levodopa for a few years if this postponed the onset of motor complications. On the other hand, withholding levodopa's sometimes substantial benefit during a period of greatest activity and productivity would be worthless if the complications appear independently of the initiation of levodopa treatment. Dopamine Receptor Agonists Three studies compared the effects of using a dopamine receptor agonist, with or without levodopa, to using levodopa alone. The dopamine agonists most commonly used for PD are pergolide, pramipexole, and ropinirole. All 3 studies compared the rate of development of motor complications in each treatment group. The design of an ongoing study, comparing early treatment with levodopa to placebo treatment, was also described. Pergolide vs Levodopa Dr. Wolfgang H. Oertel of Marburg, Germany, reported the results of the PELMOPET (PErgolide vs Levodopa MOnotherapy with Positron Emission Tomography [PET] scan) trial.[11] The participants were 44 patients in the early stages of PD (Hoehn and Yahr stage 1 to 2) with a demonstrated response to dopamine receptor stimulation (positive apomorphine test result), who had not previously been treated with levodopa for more than 2 weeks. They were randomized to be treated with either pergolide alone or levodopa alone for at least 3 years. After 1 year of treatment, patients receiving pergolide had significantly fewer and less severe motor complications than the patients receiving levodopa. However, after 3 years this difference disappeared. Moreover, the improvement in motor function provided by the drug was always greater for patients taking levodopa. The researchers also obtained fluorodopa PET scans of study patients' brains. Uptake of fluorodopa by the striatum is a measure of PD progression, decreased uptake correlating with advancing disease. There was no significant difference in the decrease in fluorodopa uptake between the 2 groups of patients. These results suggest that 1. using an agonist instead of levodopa delays the onset of severe motor complications; 2. in the long run these complications develop anyway; 3. levodopa may provide better symptom control; 4. there is no difference in disease progression between the 2 treatments. Pramipexole vs Levodopa Dr. Ira Shoulson of the University of Rochester, New York, reported the initial results of the CALM-PD (Comparison of the Agonist pramipexole vs Levodopa on Motor complications in PD) study.[12] A total of 301 patients with mild-to-moderate PD, not recently treated with levodopa, were randomized to blind treatment with either the dopamine receptor agonist pramipexole or levodopa. Unlike the previous study, treating physicians were allowed to supplement the blinded treatment with open-label levodopa if they deemed necessary; a similar proportion of patients in each group ended up receiving this supplementation. After 2 years of treatment, fewer patients in the pramipexole group developed motor complications compared with patients in the levodopa group. The levodopa group derived better motor benefit. A brain imaging scan at the beginning and end of the study showed no difference in disease progression between the 2 groups (the technique used was "beta-CIT" single photon emission computed tomography (SPECT) scan, an imaging technique measuring the amount of remaining dopamine transporter- also a marker of PD severity). This study showed after 2 years results similar to the PELMOPET study at 1 year: fewer patients developed motor complications when the initial treatment is with an agonist rather than levodopa. Remarkably, symptom control was still better in the levodopa group, even though supplemental levodopa was used in both groups to optimize treatment. This result raises several questions about treatment decisions but cannot be explained at present. As for the long-term effects of the 2 treatments, clues may come from a controlled extension of this study currently under way. Ropinirole vs Levodopa Dr. Oliver Rascol of the University Hospital in Toulouse, France, described various findings of a study comparing ropinirole to levodopa (O56 study).[13] A total of 268 patients were randomized to take ropinirole or levodopa. The use of supplemental levodopa in either group was permitted to maximize symptomatic benefit. Patients were followed up for 5 years. The incidence of dyskinesia after 5 years was significantly less in the ropinirole group compared with the levodopa group (20% vs 46%). As for effectiveness in symptom control, Dr. Rascol emphasized that the activities of daily living scores remained similar in the 2 groups. This may explain why the motor benefit from the dopamine agonist was less than from levodopa in the PELMOPET and CALM-PD studies, even though supplemental levodopa could be given to both groups of patients in these studies. If the improvement perceived by the patient (as reflected in the activities of daily living score) was the same, then the difference in motor benefit scores may not be clinically significant. Another important finding in this study was that the rate of development of dyskinesia was nearly 0 while the patients were taking ropinirole alone. Most motor complications developed after supplementary levodopa was added to the therapy. In addition, the progression of the dyskinesias after the addition of levodopa was not faster than for the patients taking levodopa alone. Thus, the benefit of using ropinirole as initial treatment is maintained even after dyskinesias develop. Earlier vs Later Levodopa Intertwined with the question of whether early PD treatment should be with an agonist or levodopa is another old but as yet unanswered question- whether delaying the start of treatment with levodopa has any influence on the development of motor fluctuations or on the course of the disease itself. Dr. Stanley Fahn of Columbia University in New York, NY, outlined the design of the ELLDOPA (Earlier vs Later Levodopa therapy) study, an ongoing study addressing the latter question.[14] A total of 360 patients in the early stages of PD are being randomized to receive levodopa therapy or placebo for 9 months. After this period they will be reexamined, and the change in severity of parkinsonism from before entering the study will be compared in the 2 groups. If levodopa, as has been widely thought, indeed provides only relief of symptoms and does not affect the course of PD, then the change in examination should be the same in both groups. Moreover, in a smaller group of patients the amount of neurodegeneration that takes place during the 9 months of the study will be assessed by comparing beta-CIT PET scans before and after treatment in each group. Medical Therapies in PD New vs Old Dopamine Agonists This session consisted of point-counterpoint style presentations on each side of 2 major current debates in this field. One subject was whether the new dopamine agonists (ropinirole, pramipexole, and cabergoline) are better than older ones (bromocriptine and pergolide). Dr. Donald B. Calne of the University of British Columbia in Vancouver, Canada, presented the arguments for the positive answer.[15] One of the main arguments is that the new agonists are at least designed to be more selective than the older ones in their action on dopamine receptors. Such selectivity often implies higher efficacy and lower frequency and range of adverse effects. Whether these advantages are real and clinically significant, unfortunately, has not been demonstrated, since there have been no direct comparisons of efficacy and adverse effect profiles between the new and the old agonists. Dr. Anthony E. Lang of the Toronto Western Hospital in Toronto, Canada, argued that the new dopamine agonists are not better than the old ones.[16] He focused on what "better" really means in this context. He argued that it is not yet clear whether efficacy, ease of use, or adverse effect profile are any better for the new agonists. He also pointed out that the new drugs are much more expensive than the old ones, and this should be included in the assessment of which drug should be used-at least until definitive studies establish a medical advantage for one drug over another. What Should Be the Initial Drug? Immediately following the discussion of new vs old dopamine agonists was a debate on whether treatment of PD should begin with agonists or levodopa. On this issue, Dr. S. Gimenez-Roldan of the Hospital General Universitario Gregorio Maranon, Madrid, Spain argued in favor of starting with agonists.[17] One argument for this position can now be considered evidence based: 3 studies described in the previous session found 3 agonists to delay the onset of motor complications associated with levodopa therapy. Another argument has been suggested by theories and laboratory evidence on the mechanisms of neurodegeneration in PD: dopamine receptor agonists may have a neuroprotective effect. This protection has been postulated to result through a variety of mechanisms, including autoreceptor stimulation, direct antioxidant effects, and decrease of subthalamic nucleus excitotoxicity. Dr. Gimenez-Roldan cautioned that starting treatment with agonists is not a blanket recommendation applicable to all patients with PD, since several factors (such as age and cognitive status) may steer the choice to levodopa instead for certain patients. Dr. Andrew J. Lees of the National Hospital for Neurology and Neurosurgery in Queen Square, London countered that treatment of PD should start with levodopa in all but those patients with young-onset PD.[18] He focused on the objective of maximizing quality of life throughout this illness. He reminded the audience that levodopa maintains its effectiveness much longer than any agonists. His main reason to avoid using agonists in the first few years was that agonists are associated with a higher rate of adverse effects. This point was questioned by Dr. Rascol, who pointed out that the rate of adverse effects was not significantly different between a dopamine agonist and levodopa in the PELMOPET, CALM-PD, or O56 studies. However, it is a widely accepted teaching that, for a given frequency of adverse effects, levodopa is more potent than any agonist in relieving PD symptoms. This belief is not, in fact, contradicted by the agonist studies: as described above, in the 2 studies that compared the motor examination scores, levodopa was more effective than the respective agonist. Dr. Lees' argument included consideration of an issue sometimes overlooked in this debate: the first few years of the disease, though marked by relatively mild symptoms, are also years during which many patients continue working or have a chance to enjoy activities, such as traveling, which they may need to give up later. Thus, treatment with a more potent drug, as levodopa appears to be, may offer a more appreciable improvement in quality of life than an agonist might. In part because of this consideration, the question of whether levodopa is indeed more "potent"- meaning providing greater relief for a given risk of adverse effects and for a given ease of use-was discussed with some interest. No one at the session offered a convincing explanation of why, in 2 of the agonist studies, the motor examination scores improved more for patients taking levodopa than for patients taking an agonist plus levodopa. After the debates, the audience was asked to express their opinion via a show of hands. Most audience members agreed that the new agonists are not clearly better than the old ones. More surprisingly, most also supported starting treatment of PD with levodopa rather than an agonist. This was remarkable because the 3 studies showed a clear delay in the onset of motor complications in patients treated with an agonist as initial therapy. A possible explanation is that ease of use (some agonists require a much slower titration of dose than levodopa before reaching the same effectiveness) and rate of adverse effects, at least as experienced by clinicians in their practice, may play a bigger role in a practicing clinicians' choices than in the conclusions of a drug study. Perhaps the most relevant comment, sobering as it was, was made by Dr. Lees at the end of the discussion. He pointed out that when considering the entire course of PD, which can span several decades, the first 5 years are usually marked by relatively minor symptoms that can be controlled adequately with either levodopa or an agonist. As he put it, "the first 5 years are easy" in terms of treatment choices. The much more difficult period is the following years, during which motor fluctuations, variation in response to levodopa, and the progression of symptoms refractory to levodopa take a more serious toll on the quality of life of patients with PD than in the first 5 years. Thus, without denying the importance of making the best use of the treatment options that we have for the initial period, he expressed hope that the search will continue for better treatments for the more advanced stages of PD.