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Continuous dopaminergic stimulation therapy in advanced Parkinson’s disease: would earlier use be beneficial?

Posted in Sponsored Feature on 8th Dec 2012

Despite developments in oral and transdermal therapy for Parkinson’s disease (PD) over the last few decades, many patients continue to suffer motor complications and dyskinesias. The standard initial treatment for this progressive neurodegenerative condition is oral levodopa. While this effectively alleviates motor symptoms, long-term treatment with oral levodopa induces motor fluctuations. Evidence shows that treatment with continuous dopaminergic stimulation (CDS) can reduce the motor complications that occur in patients receiving oral treatment and also improve non-motor symptoms (NMS).1

At an interactive symposium held at the recent 16th Congress of the European Federation of Neurological Societies in Stockholm, speakers discussed the rationale for earlier use of CDS therapy in patients with advancing PD. Dr Tove Henriksen (Denmark) outlined that three CDS therapies are available: deep brain stimulation (DBS), levodopa-carbidopa intestinal gel (LCIG) and continuous subcutaneous apomorphine infusion.

Recent studies have demonstrated reduced health-related quality of life (HRQoL) in PD patients compared with the general population,2 suggesting that better control of motor symptoms may improve patients’ QoL and that earlier introduction of CDS therapy may therefore help maintain patient QoL. As to the long-term efficacy of CDS therapy in patients with advanced PD, studies have shown that treatment with continuous subcutaneous apomorphine infusion reduces daily ‘off’ time in patients with advanced PD.3 In addition, improvements in motor complications have been demonstrated in long-term studies of LCIG,4,5 and DBS has been shown to reduce duration and severity of dyskinesias.3 However before offering these treatments, Dr Henriksen believes it is important to take into account the cost of CDS, as well as its potential side effects and complications.

Debating whether earlier intervention with CDS is justified, Professor Angelo Antonini (Italy) stressed that the issue with CDS treatment is not just that “We should do it sooner but we should also do it better to improve HRQoL for PD patients.” Earlier CDS therapy would provide more effective control of motor fluctuations earlier in the disease and alleviate NMS.

The challenge, in Professor Antonini’s view, is to find the optimum moment to start the treatment between early and advanced disease and to smooth out the delivery of the drug in order to provide more constant stimulation that mimics physiological dopamine concentrations at the synaptic cleft, thereby preventing the motor complications which the majority of PD patients develop with oral medication. Professor Antonini believes that switching from pulsatile to continuous delivery as early as possible to reproduce normal physiology would lead to fewer complications and less dyskinesia, a decline in ‘off’ time and extended ‘on’ time, thus improving QoL.

However, while patients do indeed improve dramatically with CDS, Professor Eduardo Tolosa (Spain) questioned the justification for treating the patient who has only mild fluctuations with these complex and sometimes risky therapies without long-term safety and efficacy data and without comparative studies between the various CDS strategies. While improvements in QoL in advanced PD are seen in most patients receiving CDS, not all patients experience these beneficial effects and we have no information on how many patients in the early stages of the disease will actually improve with CDS. For Professor Tolosa the key issue is therefore that these CDS-based therapies are given to the right patients.

In addition, the side effects of complex CDS therapies are numerous − including leg oedema, psychiatric problems, and postural hypotension. These are accepted by patients with advanced disease because the treatment improves their disability dramatically. But to apply treatments with these side effects to patients in the early (mild) stages of PD is a decision that should not be taken lightly, in Professor Tolosa’s view.

Another consideration is that very little is known about the natural history of the motor complications of PD. Their impact on QoL is hard to predict so for any individual patient it is difficult to forecast their level of disability in ten years’ time. The question is how to identify those patients with progressive disability who have the phenotype that will benefit from earlier intervention. Professor Tolosa noted that it appears that younger patients, and those with low bodyweight and low BMI, are more likely to suffer motor complications.

In the view of symposium chairman Professor Ray Chaudhuri (UK), many are persuaded of the potential benefits of early intervention with CDS in PD. Others, however, need more evidence before they are convinced. It is clear that CDS is accepted as a valuable treatment in advanced PD. Whether or not it should be started at an earlier stage of the disease requires further study.

References

1.      Antonini A, et al. The progression of non-motor symptoms in Parkinson’s disease and their contribution to motor disability and quality of life. J Neurol 2012; Jun 19.

2.      Winter Y, et al. Quality of life in Parkinson’s disease in Europe: a multi-centre study of the EuroPa Study Group. MDS Abstract of the 16th International Congress of Parkinson’s Disease and Movement Disorders, Ireland, 2012. Abstract 945.

3.      Antonini A, et al. A 5-year prospective assessment of advanced Parkinson disease patients treated with subcutaneous apomorphine infusion or deep brain stimulation. J Neurol 2011;258:579-85.

4.      Zibetti M, et al. Long-term duodenal levodopa infusion in Parkinson’s disease: a 3-year motor and cognitive follow-up study. J Neurol 2012; Jul 8.

5.      Nyholm D, Klangemo K, Johansson A. Levodopa/carbidopa intestinal gel infusion long-term therapy in advanced Parkinson’s disease. Eur J Neurol 2012;19:1079-85.

A grant was provided by Britannia Pharmaceuticals Ltd as a contribution towards the production and design costs of this article, which was written by Helen Lawn & Associates. Britannia Pharmaceuticals co-sponsored the satellite symposium held on 9th September during the recent 16th EFNS Congress held in Stockholm.

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