Optimization of L-dopa therapy at the onset of effect fluctuations

Levodopa (L-dopa) is still considered the gold standard in the treatment of Parkinson’s disease. Among them, good symptom control with high quality of life can be achieved for the patient over a long period of time [1]. However, after initial therapeutic success, fluctuations in effect are almost inevitable in the course of treatment. The consequences of the occurring complications are mainly motor fluctuations (MF) and dyskinesias.

State of the Art in Parkinson’s Therapy

Parkinson’s disease is now understood as a spectrum disease; the term Parkinson’s encompasses a group of heterogeneous disorders that exhibit a diverse spectrum of motor and non-motor symptoms. Whereas non-motor symptoms – such as sleep disturbances, pain or changes in mood – used to be referred to as secondary symptoms, it must now be stated that these represent one of the main problems of Parkinson’s disease, at least in the long-term course. These symptoms show variable response to dopaminergic substitution therapy. It is now believed that up to 15% of PDs have a genetic background (at least as a risk factor for developing PD). There is variable progression of neurodegeneration and variable clinical course of disease – this fact makes it particularly difficult to make clinical predictions; there is a weak or even absent relationship between clinical phenotype and pathology. Clinical or data-based attempts to identify Parkinson’s subtypes, which can then be used to estimate prognosis for the clinic, often fail. An exception is often tremor-dominant Parkinson’s disease, which usually has a good prognosis [2]. Even mono-genetic Parkinson’s syndromes can vary in their clinical presentation.

The basis of Parkinson’s treatment to date is dopaminergic substitution therapy with levodopa, always in combination with the decarboxylase inhibitors carbidopa or benserazide. Decarboxylase inhibitors inhibit the peripheral degradation of L-dopa, thereby increasing its bioavailability [3]. L-dopa is converted to dopamine in the brain and taken up into the dopaminergic terminals, released as dopamine, and in particular stimulates the postsynaptic dopamine receptors D1 and D2. This results in the basal ganglia-motor cortex-thalamic control circuit, which regulates motor function, being restored to its physiological function [4]. If the control circuit system is stimulated with too little dopamine, a braking effect occurs, whereas an excess of dopamine tends to accelerate the movements. This is also the basis for the occurrence of dyskinesias or dystonias and hyperkinetic movement disorders. In addition, the short half-life of L-dopa substitution therapy is responsible for the occurrence of fluctuations in its effect, which leads to non-physiological pulsatile stimulation of dopamine receptors. Ultimately, the dopamine vesicles, which are not well filled, also play an important role in the occurrence of effect fluctuations.

Start of therapy

In elderly patients >70 years and or those with comorbidity, therapy of Parkinson’s disease is usually started with levodopa. Younger people and/or those without comorbidities or with mild symptoms often start treatment with an MAO-B inhibitor and/or a dopamine agonist (Fig. 1) [5,6]. However, patients who start with an MAO-B inhibitor almost always require additional L-dopa during the course of their treatment.

The advantage of dopamine agonists vs. levodopa is that they have a longer half-life and are provided to the brain more consistently. However, neuropsychiatric side effects, daytime sleepiness or sudden sleep attacks, and edema may occur. V.a. the occurrence of impulse control disorders is typical and must be avoided [6].

When the honeymoon is over

In addition to anamnesis with targeted inquiries about effect fluctuations in the patient and caregiver, questionnaires (Wearing-off Questionnaire by Mark Stacy et al.) can be used, which help to detect significantly more effect fluctuations than can be found out by questioning alone. In recent years, it has been shown that levodopa therapy, which appears so successful at the beginning of the disease (honeymoon phase), ultimately has an unfavorable effect on motor function. The therapeutic window for L-dopa is narrowing, due to the progression of neurodegeneration and the associated sensitization of dopamine receptors. Thus, on the one hand, Parkinson’s disease is characterized by a natural neurodegenerative course; on the other hand, its treatment is further complicated by the occurrence of therapy-associated complications over time. Motor fluctuations are observed in 20-30% of patients as early as one to two years after initiation of levodopa therapy, and the proportion is as high as ≥50% after 5 years [7].

As the disease progresses, there is a reduction in dopaminergic terminals in the CNS. Other types of neurons that are also capable of metabolizing levodopa must compensate, such as serotonergic neurons. These neurons produce not only serotonin but also dopamine, but can only reuptake serotonin, i.e. the released dopamine remains in the synaptic cleft, accumulates there and leads to fluctuating, no longer stable dopamine levels in the striatum. These, in turn, lead to sensitization of postsynaptic receptors and downstream postsynaptic dopaminergic neurons, resulting in various changes, including increased sensitivity in the motor system with the appearance of dyskinesias. In addition, there are also disturbances of dopaminergic circuits of cognitive and emotional regulation, which can lead to psychiatric and behavioral disorders in patients. In addition, alpha-synuclein pathology also spreads to non-dopaminergic core areas of the brain, leading to their dysfunction (review 1) .

No disease-modifying effect due to levodopa

A 2019 Dutch study supported that levodopa is neither neurotoxic nor neuroprotective [8]. In the delayed-start design, one group is treated immediately and one delayed with a substance that was thought to be disease-modifying. If there were disease-modifying therapy, the curves indicating disease progression should have been offset in parallel after delayed use. Instead, the curves converged: There was a symptomatic effect – the patients in the described levodopa study on levodopa had less disease severity on the UPDRS scale (Fig. 2A) . The group with delayed levodopa use had this effect as well, just later, and at the end everyone was at the same level. This was also expressed in terms of quality of life (Fig. 2B) – the delay resulted in patients from this group having a poorer quality of life over a longer period of time. Thus, in terms of quality of life and symptom reduction, there is no reason to withhold L-dopa from patients. It is the most potent substance and it is the substance that brings the best quality of life in the early stages. Delayed use has no advantage with regard to the effect of the substance.

Regarding long-term complications, a study over a follow-up period of up to 14 years investigated whether initiation with a dopamine agonist vs. levodopa alone vs. selegiline provided a long-term benefit [9]. There, a small advantage of bromocriptine was seen over a short period of time, but this quickly disappeared, after which there was no efficacy advantage for the dopamine agonist over levodopa therapy in long-term therapy. Most patients require levodopa over the long treatment period after a few years anyway. There were also no differences in the occurrence of effect fluctuations (mainly dyskinesias).

Quality of life is withheld

Italian researchers, together with colleagues from Ghana, matched Parkinson’s cases from Italy and the African country, starting from the assumption that in Europe, in a well-developed health system, one does not delay the use of a therapy, while in Ghana this is not guaranteed in this form [10]. There, Parkinson’s patients cannot easily be diagnosed and therapy is also delayed due to a lack of neurologists and financial resources.

In relation to the presumed onset of the disease, they compared how long the patients remained undiagnosed, from when they were then treated with levodopa in Italy or Ghana, and when secondary complications such as wearing-off or dyskinesia finally occurred. The Italian patients had been diagnosed after an average of 3.5 years from symptom onset and then received L-dopa. Wearing-offs occurred after about 5.5 years. The Ghanaian patients, on the other hand, remained undiagnosed for a very long time, followed by a period of diagnosis, during which they were not given any medications (forced to save money), until the condition worsened. Levodopa was given to them after an average of 5.9 years, but wearing-off and dyskinesia set in after only a few months here. Thus, the only effect of saving up was that the honeymoon phase was very short, depriving patients of a period with a good quality of life.

If nothing else, the results of this study have reinforced the assumption that the extent of neurodegeneration in the striatum, in particular, is crucial for determining when fluctuations and dyskinesias occur in the context of L-dopa therapy.

Counteract motor complications

Motor fluctuations (MF) are associated with poorer quality of life [11]. As already mentioned, they are caused in particular by the pulsatile effect of levodopa and when its dosage is too high. To counteract this, it is recommended to set the L-dopa dose as low as possible, with the longest possible duration of action (continuous dopaminergic stimulation, CDS) [12]. One option to reduce MF is to use agents with long-acting dopamine receptor stimulation as an add-on to L-dopa [13]. However, there is a risk of side effects, with less overall benefit in terms of movement disorders than with L-dopa.

The problem with dopamine release: in advanced PD, dopamine storage capacity is depleted, and highs and lows of L-dopa plasma levels lead more quickly to dyskinesias and off-times due to a lack of dopamine vesicles. For practitioners, this means that the levodopa dose should not be increased because this also increases the risk of dyskinesias, and that likewise an increase in frequency of L-dopa administration should be avoided because this does not change the problem of plasma level peaks without levodopa dose adjustment (reduction), with the additional increasing influence of meals on levodopa levels.

The first motor fluctuation in the course of the disease often manifests itself as the so-called early morning off, in which the effectiveness of the therapy is no longer sufficient in the second half of the night or in the morning [14]. The reason for this is the decrease in endogenous dopamine release (about 40%) at night due to the circadian rhythm [15]. As the disease progresses, the wearing-off then also occurs during the day, which is due to the short half-life of levodopa and the decreasing storage capacity of the presynaptic neurons [16]. The delayed onset of action of levodopa (Delayed-On), results from delayed gastric emptying and impaired intestinal absorption of levodopa. Accordingly, the off-time is composed of the Wearing-Off and the Delayed-On, whereby the Delayed-On can clearly predominate [6].

DDC, COMT and MAO-B inhibitors

A number of complementary potent agents are now available to optimize the mechanism of action of levodopa: Dopa decarboxylase inhibitors (DDC inhibitors, carbidopa, benserazide), catechol-O-methyltransferase inhibitors (COMT inhibitors, tolcapone, entacapone, opicapone) and monoamine oxidase B inhibitors (MAO-B inhibitors, selegiline (not available in Switzerland), rasagiline, safinamide) [17]. Dual inhibition with add-on administration of a DDC plus a COMT inhibitor to levodopa may allow a 30-50% reduction in plasma variability [18]. A welcome additional effect of dual inhibition is also a possible reduction in L-dopa dose, which is associated with a reduction in MF risk.

The primary therapeutic goals in the management of MF include appealingly good and consistent mobility, the best possible freedom from motor and non-motor symptoms, and the preservation of independence. Possible therapy adjustment options for Wearing-Off include.

• the administration of dopamine agonists,
• The greater fractionation of L-dopa doses,
• the use of levodopa retard preparations (primarily at night) and
• the combination with COMT inhibitors or MAO-B inhibitors [5].

COMT inhibitors act like decarboxylase inhibitors in the periphery: by inhibiting catechol-O-methyl transferase (COMT), they prevent the degradation of levodopa to 3-O-methyldopa (3-OMD), thereby increasing its bioavailability in plasma [6]. In contrast to entacapone and opicapone, tolcapone also has an additional minor effect on COMT in the brain, although it is of secondary importance today due to potential hepatotoxicity. MAO-B inhibitors increase striatal dopamine levels by blocking cerebral degradation of dopamine via monoamine oxidase B. However, as described, for MAO-B inhibitors to be effective, it is important that a minimum supply of striatal dopamine is present [6].

The choice of COMT inhibitor should be individualized and adapted to the patient’s disease situation. It is important to note that approval status also plays a role: Opicapone and entacapone can be used as add-on therapy to levodopa plus a decarboxylase inhibitor (DDCI) in patients with motor “end-of-dose” fluctuations [19,20]. Tolcapone, on the other hand, is approved only in combination with levodopa plus a decarboxylase inhibitor in patients who have fluctuations in mobility and do not respond to or cannot tolerate other COMT inhibitors because of its liver toxicity [21].

Opicapone has a very short half-life of 1.0-1.4 h, but a long duration of action due to its long inhibition half-life of >100 hours [22]. After 24 h, COMT activity is still reduced by approximately 65%. This duration of action has the advantage of a long-lasting stable COMT inhibition and allows a daily single dose, whereas tolcapone is taken 3 times a day and even up to 6 doses a day are not uncommon with entacapone [22]. Entacapone also has a short half-life (approximately 2.5 h) and, in addition, a short inhibition half-life and therefore must be taken with each dose of levodopa. Because the short half-life means that the effect of COMT inhibition varies, entacapone, unlike opicapone, risks reducing the range of variation in levodopa levels less than intended [6].

COMT inhibitors can increase and smooth plasma levels of L-dopa. The double-blind, randomized STRIDE-PD trial therefore investigated whether initiation of combined levodopa/carbidopa/entacapone (LCE) therapy versus levodopa/carbidopa therapy alone could delay the onset of dyskinesias by smoothing drug levels (reduced pulsatile stimulation) [23]. However, the primary endpoint of the study was missed: there was even a significantly shorter time to onset of dyskinesias (hazard ratio, HR, 1.29; p=0.04) and significantly more frequent dyskinesias (42% vs. 32%; p=0.02) in patients on LCE compared to those on levodopa/carbidopa [24]. In addition, motor complications and dyskinesias were not found to be associated with duration of LD therapy but with longer disease duration and with higher LD doses [10].

For the use of COMT inhibitors in practice, this means that the levodopa dose should be selected only as high as required for a satisfactory effect. The dosage should take into account the patient’s gender and weight. This was recently demonstrated in a study by Ferreira et al. [26] ( Fig. 3). In this work, the authors demonstrated that patients receiving an additional 50 mg opicapone under 5× 100 mg L-dopa/carbidopa had the most stable pharmacokinetics and thus probably the best continuous dopamine receptor stimulation under 100-50-100-50-100 mg L-dopa/CD. The pharmacokinetics, i.e. “peaks and troughs” and 4× 100 mg LD/CD looked somewhat worse. Thus, it can be learned from this study that in some patients receiving opicapone for wearing-off symptomatology, LD/CD must be reduced and the optimal distribution of LD/CD must be found. Data from the clinical trials also show that in patients at the onset of motor fluctuations (MF <1 year) and in less advanced disease stages (Hoehn & Yahr stage <2.5), off-time is reduced more with opicapone than on average in the trials [27]. Follow-up presentations by the patient in the first weeks after initiation of therapy with a COMT inhibitor are advisable in order to adjust the L-dopa dose if necessary [6].

Conclusion

Levodopa is the gold standard in the treatment of Parkinson’s disease and is administered to almost all Parkinson’s patients during the course of their disease. However, the development of motor fluctuations with this therapy is common. Various agents (DDC, COMT, and MAO-B inhibitors) are available to treat these fluctuations and are intended to optimize L-dopa therapy. Of particular note here is the ability of COMT inhibitors, especially shown in the recent study by Ferreira et al. with opicapone [26], to smooth plasma L-dopa levels, restoring continuous dopaminergic stimulation. Which therapy adjustment is most suitable must be determined on an individual basis.

Take-Home Messages

• The therapy of Parkinson’s disease must be individualized with regard to the expected effect on the disabling symptoms.
• The likelihood of adverse effects should be considered, taking into account the patient’s age, stage of disease, concomitant diseases, and concomitant medications.
• Selection and escalation of medication or interventions should be made with the goal of maintaining an optimal functional state (honeymoon phase) for as long as possible.
• Long-term therapy with L-dopa is associated with fluctuations in effect, yet there is no better treatment option and it should therefore not be withheld from patients.

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InFo NEUROLOGY & PSYCHIATRY 2023; 21(1): 10-15.