HILDE-ULRICHS-STIFTUNG FÜR PARKINSONFORSCHUNG

HILDE-ULRICHS-STIFTUNG FÜR PARKINSONFORSCHUNG | Projekte | L-Dopa oder Agonisten ?

Unser Vorsitzender des Stiftungsbeirates Michael Kelly aus Frankfurt/Main hat aufgrund von umfangreichem Literaturstudium (bis November 2005) Aussagen zusammengestellt, die sich auf die zentrale Behandlungsfrage von Parkinsonkranken bezieht: L-Dopa oder Agonisten ?. Der gebürtige Ire hat die nachfolgenden Aussagen in seiner Muttersprache Englisch verfaßt und in der Mitgliederzeitung der englischen jungen Parkinsonkranken namens SPRING veröffentlicht, deren Mitglied er ist.

Stand: November 2005

Initial treatment of choice: L-dopa or agonists?

More than 30 years have elapsed since L-dopa therapy became widespread and agonists have been available for about 25 years. Despite numerous studies, many questions remain about what medication should be preferred initially. There is little doubt about the substantial motor benefits associated with L-dopa and its clearly superior action compared to agonists in alleviating a broad range of symptoms including increased muscle tone, tremor and slowness of movement. Agonists are less potent and generally not as well tolerated as L-dopa. The two main issues associated with use of L-dopa are dyskinesias and neurotoxicity. At an early stage in treatment, doctors and patients are faced with the difficult issue of whether to delay or restrict use of L-dopa with a view to reducing dyskinesias and circumventing potential neurotoxicity.
After some period of using L-dopa, generally in the range of 5-10 years, patients develop complications characterized by on/off fluctuations, dyskinesias –uncoordinated, involuntary writhing movements of limbs and head, freezing, postural instability to name but a few. Dyskinesias can take many forms, chorea and dystonia being the most usual associated with L-dopa. Furthermore, the time at which dyskinesia occurs, peak dose or diphasic related, also enters the picture, complicating matters further. L-dopa dyskinesias are generally associated with nigrostrial dopamine denervation, indicating a loss of function in dopamine modulation in the motor loops of the basal ganglia. Dyskinesias almost invariably precede motor fluctuations by a number of years.
A considerable amount of published data appears to favor the use of agonists, linking dyskinesias with L-dopa and pointing to a relative absence of dyskinesias when using agonists. It is also claimed that L-dopa loses its effectiveness after prolonged use. However, detailed investigations seem to indicate that L-dopa largely maintains effectiveness in treating symptoms such as tremor and bradykinesia while symptoms that never respond well to L-dopa in the first place such as postural instability and freezing become more prominent after some years as the disease profile unfolds over time. In addition, there is evidence to suggest that complications ascribed to L-dopa may arise independently anyway so that foregoing its use at a period in life when it might confer maximum benefit may be a needless waste.
Representing some of the most extensive investigations carried out todate, reports of three studies presented at the 6th International Congress on PD and Movements Disorders in Barcelona in June 2000 compared the effects of using a dopamine receptor agonist, with or without L-dopa, to using L-dopa alone. All three studies compared the rate of development of motor complications in each treatment group.

Pergolide vs L-dopa (PELMOPET study)
44 patients, randomized into two groups, received either Pergolide alone or L-dopa alone for 3 years.
After one year of treatment, the Pergolide group had substantially less dyskinesias, however after 3 years, no difference was apparent. Motor function improvement was better in the L-dopa group. No difference in fluorodopa uptake was apparent between the two groups.
This would suggest that agonists may delay onset of dyskinesias but do not prevent same and do not alter relative progression of the disease.

Pramipexole vs L-dopa (CALM PD Study)
A trial with over 300 patients over 24 months, average age 61, evaluated Pramipexole vs L-dopa, in this case with the difference that the agonist could be supplemented by L-dopa. Again, fewer complications were found after 2 years in the agonist group, 49% of the L-dopa group and 72% of the agonist group remained free from motor complications, dyskinesias were evident in 10% of the agonist group as against 31% in the L-dopa group. Motor benefits were enhanced in the L-dopa group. Despite L-dopa being used together with an agonist. SPECT testing showed no difference in progression between the two groups after 2 years.

Ropinirole vs L-dopa (056 Study)
In a third trial, 268 patients were given either Ropinirole or L-dopa, supplemented in both groups by L-dopa as necessary. The trial was over 5 years at the end of which the agonist group showed significantly less dyskinesias (20% vs. 46%).
The literature contains many references to the beneficial effects of Amantadine in alleviating L-dopa induced dyskinesias. Amantadine appears, apart from its antiglutamatergic action, to play a role in suppressing inflammation, whether this is relevant to dyskinesias is at present unknown.

Neurotoxicity of L-dopa

A considerable body of literature addresses the issue of neurotoxicity of L-dopa/dopamine. Dopamine oxidizes either spontaneously in the presence of transition metals or by enzymatic action to yield a series of reactive compounds including quinones and semi-quinones, structurally similar to MPTP and MPP+, the latter being highly neurotoxic. It is postulated that increased, indiscriminate levels of dopamine in the brain can lead to increased neurotoxicity, especially when anti-oxidant scavenger levels drop, as is the case in aging.
N-methyl-(R)-salsolinol occurs in the brain as a breakdown product of dopamine, formed by condensation of dopamine with pyruvic acid or with acetaldehyde. This isoquinoline is capable of inducing PD in animals, with behavioural and pathological changes very similar to PD in humans. Furthermore, there is evidence that dopamine, in the presence of transition metals, can give rise to 6-hydroxydopamine (6-OHDA), a potent neurotoxin.
Damage from dopamine appears to depend to some extent on the effectiveness of anti-oxidant protective mechanisms, in particular the ability to detoxify the OH ˉ radical, one of the main disruptive agents in biological environments.

Disease progression

Neither L-dopa nor dopamine agonists appears to have any appreciable influence on the progression of the disease, despite a number of claims to the contrary. Evidence of neuroprotective action associated with L-dopa, agonists and other substances is oftentimes less than compelling and needs to be treated with caution.
Apart from the agonist/ L-dopa issue per se, the question arises whether postponing L-dopa has an influence on disease progression. A recently published report (Fahn S., J. Neurology 2005; Oct., 252. Suppl 4: P 37-42) on the ELLDOPA trial (an extensive study involving 361 patients and running for 42 weeks) concluded that L-dopa does not hasten disease progression, rather the contrary may be the case. Furthermore, it was found that the occurrence of dyskinesias might be dose dependent. Somewhat contrary to clinical findings, the trial showed that L-dopa causes a more rapid decline in dopamine transport to nigrostriatal terminals in the striatum. This latter finding could be interpreted as an indication of greater potential to develop dyskinesias in the L-dopa group, though they had not yet become clinically manifest.

L-dopa and life expectancy

There is no evidence that L-dopa shortens life expectancy, rather the contrary appears to be the case. A very long-term study carried out by Rajput and Uitti in Canada assessed 934 patients over 22 years, some individual cases running to 32 years. The results indicated that earlier use of L-dopa resulted in improved survival compared to patients receiving L-dopa later. This outcome is in line with the ELLDOPA results cited elsewhere in this article.

Agonists currently in general use

Note: dose equivalents are indicative only and may vary considerably in individual cases
Agonists have advantages in terms of considerably longer half-lives (Cabergolin up to 65 hours) and are not affected by adsorption kinetics or gastric motility in the same way as L-dopa. In the decision to go the L-dopa or agonist route, account needs to be taken also of the side effects associated with agonists. The principal side effects are nausea and vomiting, postural hypotension, hallucinations and confusion, exacerbation of dyskinesias, tissue fibrosis (ergot-derived agonists), sudden sleep episodes, peripheral edemas, and disruption of circadian rhythms. A detailed look at these and a comparison of profiles of different agonists is beyond the scope of this article.
Evidence suggests that L-dopa/dopamine has a much broader range of effects than dopamine agonists per se and that functionality in the more or less complete absence of dopamine is very severely impaired. Furthermore, agonist stimulation of D1 receptors (related to reward behavior, also reported to promote dyskinesias) appears to lead to a lack of response as habituation sets in so that eventually use of L-dopa becomes inevitable. It is then a question of deciding when this point is reached. This depends on age, degree of impairment and interference with activities of daily living. Manifesting symptoms also have to be taken into account. With PD usually extending over decades, the first 5 years are relatively easy and symptoms can be treated with an agonist or L-dopa. The difficulty arises subsequently when symptoms become more severe. In this phase, L-dopa is difficult to avoid.
Apart altogether from scientific considerations, it is well to keep in mind that pharmaceutical companies have a vested interest in promoting agonists instead of L-dopa. Most agonists are still patent protected and sell at a substantial premium to L-dopa. Equivalent doses of agonists retail at about five or more times the price of L-dopa (Germany).
Summary: Evidence points to increased dyskinesias when L-dopa is used as initial medication. However, L-dopa inevitably enters the picture sooner or later, the point of entry depending on age, degree of disability and functional imperatives. There is little or no evidence that L-dopa affects disease progression, indications are that timely use of L-dopa prolongs life expectancy. L-dopa appears to be capable of generating neurotoxins so that consideration should be given to the use of Amantadine and anti-oxidants concomitant to using L-dopa. Potential side effects of agonists should not be ignored.
M. Kelly November 2005
Note: Literature references are omitted in the interests of brevity. Please contact M. Kelly (michael.kelly@t-online.de) with questions or comments

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