The treatment of L-dopa associated effect fluctuations.

Parkinson’s patients suffer the most from effect fluctuations. However, it is not possible to predict when this phase begins due to the individual course of the disease. Several starting points have now been detected to maintain the effect of L-dopa. Interventions with COMT inhibitors are among the promising options to improve quality of life in the presence of drug fluctuations.

The introduction of L-dopa has revolutionized the armamentarium in neurology. Although it has been on the market for a long time, it remains the therapeutic gold standard and is considered the best-performing Parkinson’s drug that is well tolerated. Eventually, in the course of the disease, the use of L-dopa becomes necessary in almost every patient. Last but not least, it is a cost-effective intervention, affirmed Prof. Werner Poewe, MD, Innsbruck (A). The only drawback is the motor complications that occur during chronic L-dopa therapy. And these are not to be disregarded. Depending on the study base, the rate of affected individuals after five years of treatment ranges from 30-90%. In addition to L-dopa treatment, dosage, disease duration, and age are established risk factors.

A survey of 173 Parkinson’s disease patients treated with L-dopa and a ≥six-year duration of disease found that effect fluctuations, mood impairment, and drooling were among the three most bothersome symptoms. Effect fluctuations are subject to different pathogenetic factors. For example, dysphagia, variable gastric emptying due to gastroparesis, competition for intestinal absorption with dietary amino acids, or competition at the blood-brain barrier with dietary amino acids for BBB transport, and a short half-life may adversely affect L-dopa action. The short half-life can be varied using peripheral metabolism by aromatic L-amino acid decarboxylase (AADC) or catechol-O-methyltransferase (COMT).

COMT inhibition can mitigate effect fluctuations

The first COMT inhibitors were approved in the late 20th century. Tolcapone is peripherally and centrally effective, but now used only as a second-line agent because of its hepatotoxicity. In this case, close monitoring is obligatory, the expert emphasized. Entacapone is only peripherally effective and thus weaker than tolcapone, but does not exhibit hepatotoxicity. The introduction of opicapone then provided the desired improved effect without toxicity. This agent is a peripherally acting, selective COMT inhibitor with very high binding affinity and a slow dissociation rate of the opicapone COMT complex. Due to the long duration of action, once-daily application is sufficient.

Studies have shown that off-time could be reduced by more than an hour on average. In 37% of those affected, the reduction was even ≥2 hours. Dyskinesia was the most common adverse effect, which was well controlled by L-dopa dose reduction. In addition, early use seems to make sense in the presence of effect fluctuations, Poewe summarized.

Congress: FomF Neurology Update