Since the discovery that the gold standard treatment in Parkinson’s disease (PD), oral levodopa, contributes to motor fluctuations, the treatment strategy of delivering dopaminergic drugs in a continuous manner has been investigated. Motor fluctuations are believed to be the result of a combination of progressive denervation of the striatum with advancing disease and erratic gastric emptying with oral levodopa, which leads to peaks and troughs in plasma levodopa concentration and thus pulsatile stimulation of dopaminergic neurons. Methods have been developed to provide continuous dopaminergic stimulation, such as the delivery of apomorphine by subcutaneous infusion and levodopa/carbidopa by intestinal gel infusion. These therapies have been shown to significantly reduce ‘off’ time and improve motor fluctuations, and therefore have been a major advance in the management of PD.
Parkinson’s disease, levodopa, continuous dopaminergic stimulation, subcutaneous apomorphine infusion, levodopa/carbidopa intestinal gel infusion
Lessons Learned about Levodopa
Motor fluctuations in Parkinson’s disease (PD) were described as early as 1969 by Cotzias et al.1 Subsequent studies showed that many motor fluctuations were associated with low plasma levodopa levels (troughs) that occurred between oral doses of levodopa.2This phenomenon was called the end-of-dose deterioration or ‘wearing-off’ effect. In the 1970s and 1980s, clinical pharmacology research provided a great deal of information about oral levodopa and its relationship to the ‘wearing-off’ effect.
Levodopa benefits the patient from the very first dose but requires a few weeks to reach optimum effect. The stronger the initial response to the drug, the more prominent the subsequent motor fluctuations.3 Increasing the dose of levodopa has been shown to prolong the duration of benefit, but does not increase the amplitude of response, and generally, the motor response wears off when plasma levodopa level drops to 50 % of the peak level, irrespective of the duration of benefit.4
The ‘On-off’ Phenomenon
The most common manifestation of the ‘on-off’ phenomenon is inter-dose or peak-dose dyskinesia, which occurs at a rate of approximately 10 % per treatment year. As a result, after 10 years of oral levodopa treatment, almost all patients who are on significant doses of levodopa will have developed some dyskinesias.5 Another form of dyskinesia is biphasic dyskinesias, which are much less frequent, partly because modern pharmacotherapies help to reduce their severity. These are particularly troublesome in young-onset patients, are extremely disabling and much more difficult to treat than peak-dose dyskinesias. ‘Off’-period dystonia is another form that is often forgotten. Therefore, dyskinesias are not just one simple pattern of peak-dose dyskinesias.
In the 1980s, it was not clear whether ‘off’ periods were treatable. One theory was that during ‘off’ periods, patients were unresponsive to dopaminergic drugs, even at a high dose. However, this view began to be challenged by studies using continuous delivery of dopaminergic drugs.
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Andrew Lees has acted as a consultant for Genus and has served on the advisory boards of Novartis, Teva, Meda, Boehringer Ingelheim, GlaxoSmithKline (GSK), Ipsen, Lundbeck, Allergan, Orion, Bial, Noscira and Roche. He has received honoraria from Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, Bial, Noscira and Roche, as well as grants from PSP Association and Weston Trust – The Reta Lila Howard Foundation.
Andrew Lees, Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK. E: firstname.lastname@example.org
The V International Forum on Parkinson’s Disease (Helsinki, Finland, 6–7 May 2011) was funded by an unrestricted educational grant from Abbott. Abbott funded the development of this supplement by ESP Bioscience (Crowthorne, UK). Emily Chu and Nicole Meinel of ESP Bioscience provided medical writing and editorial support to the author in the development of this publication. Abbott had the opportunity to review and comment on the publication’s content; however, all decisions regarding content were made by the author.