Dopamine agonists early monotherapy for the delay of development of levodopa-induced dyskinesias

Abstract

Dyskinesias are common, often disabling motor complications emerging in Parkinson’s disease following chronic levodopa treatment. Common views associate the development of dyskinesias both with progressive loss of striatal dopamine nerve terminals and with intermittent delivery of the short half-life levodopa. Thus, according to continuous dopaminergic stimulation theory, dopamine agonists having half-lifes longer than levodopa would minimize the risk of the development of dyskinesias. The article highlights some interesting aspects of the clinical trials testing dopamine agonists monotherapy as a strategy that can reduce the risk of motor complications, and raises some concerns in terms of their early use in Parkinson’s disease treatment to prevent or delay dyskinesia. Finally, we emphasize the need for reconsideration of arguments against use of levodopa as a starting therapy for Parkinson’s disease.

Keywords:

• continuous dopaminergic stimulation
• dopamine agonists
• levodopa-induced dyskinesias
• long-term results
• Parkinson’s disease

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Continuous dopaminergic stimulation theory claims that dopaminergic drugs with half-lifes longer than levodopa produce fewer motor complications such as dyskinesias, giving in that way the theoretical background for early monotherapy with dopamine agonists (DAs) in early patients with Parkinson’s disease (PD).

• Unfortunately, not all results of the large long-term clinical trials of DAs early administration were equally promising.

• DAs do not seem to reduce the risk of dyskinesias once levodopa is added, but rather provide benefit by delaying the time until levodopa treatment is required. This delay seems to be at the cost of motor improvement and quality of life, both rendering the addition of levodopa inevitable after few years of treatment.

• Taking also into account the safety profile of DAs, as well as that a number of non-motor symptoms, such as depression, respond to the dopamine replacement therapy in general, and not only to DAs as originally thought, a more skeptical approach regarding DAs monotherapy seems to be a more realistic option in terms of PD early treatment.

• Since substantial evidence suggests that the development of dyskinesias is related, apart from the extent of the denervation, to the amount of the dopamine replacement therapy such as levodopa, it seems reasonable when starting treatment of PD to aim mainly to retain the lower possible levels of dopamine replacement therapy, considering at the same time the quality of life of the patient.

• Moreover, the significant reduction in levodopa-induced motor complication demonstrated in EARLYSTIM trial, which evaluated the benefit of deep brain stimulation early in the course of PD, could be supportive to initiating pharmacotherapy with levodopa, taking advantage of its superiority in controlling PD symptoms.

• DAs especially in extended released preparations, as well as in transdermal delivery systems, are appropriate pharmacokinetic interventions in the later stages of the disease when motor complications interfere with the patient’s quality of life.