Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications

Levodopa-induced motor complications are a common source of disability for patients with Parkinson's disease. Evidence suggests that motor complications are associated with non-physiological, pulsatile stimulation of dopamine receptors. In healthy brains, dopamine neurons fire continuously, striatal dopamine concentrations are relatively constant, and there is continuous activation of dopamine receptors. In the dopamine-depleted state, standard levodopa therapy does not normalise the basal ganglia. Rather, levodopa or other short-acting dopaminergic drugs induce molecular changes and altered neuronal firing patterns in basal ganglia neurons leading to motor complications. The concept of continuous dopaminergic stimulation proposes that continuous delivery of a dopaminergic drug will prevent pulsatile stimulation and avoid motor complications. In monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's disease, long-acting or continuous infusion of a dopaminergic drug reduces the risk of motor complications. The current challenge is to develop a long-acting oral formulation of levodopa that provides clinical benefits but avoids motor complications.     

Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson's disease

Continuous dopaminergic stimulation is a therapeutic strategy for the management of Parkinson's disease, which proposes that dopaminergic agents that provide continuous stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. Dopaminergic neurons in the basal ganglia normally fire in a random but continuous manner, so that striatal dopamine concentrations are maintained at a relatively constant level. In the dopamine-depleted state, however, intermittent oral doses of levodopa induce discontinuous stimulation of striatal dopamine receptors. This pulsatile stimulation leads to molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These effects are reduced or avoided when dopaminergic therapies are delivered in a more continuous and physiologic manner. Studies in primate models and patients with Parkinson's disease have shown that continuous or long-acting dopaminergic agents are associated with a decreased risk of motor complications compared with short-acting dopamine agonists or levodopa formulations. Continuous dopaminergic stimulation can be achieved with a continuous infusion, but infusion therapies are cumbersome and not likely to be acceptable to patients with early disease. The current challenge is to develop a long-acting oral formulation of levodopa that provides comparable anti-parkinsonian benefits without motor complications.     

Is there room for new non-dopaminergic treatments in Parkinson’s disease?

The contribution of non-dopaminergic degeneration to disability in Parkinson’s disease (PD) is still debated. It has been argued that no additional advance can be expected in the management of PD by the development of new dopaminergic agents and suggested that future research should mainly focus on therapies targeting the non-dopaminergic systems involved in the pathogenesis of levodopa resistant motor and non-motor symptoms. We believe this is only partially true and the achievement of a stable dopaminergic restoration and modulation of the dopaminergic system is still an important, unmet need of current pharmacological therapies in PD. Currently available oral levodopa and dopamine agonist medications provide insufficient benefit, as the therapeutic window progressively narrows and motor fluctuations eventually develop in most patients. Conversely, the application of infusion and surgical therapies is limited by selective indications and possible irreversible adverse events and device-related problems. Research of new, safer and less invasive strategies, able to modulate the dopaminergic circuits, would certainly improve the management of motor complications, and most importantly such treatments would be also beneficial to axial and non-motor symptoms, which are universally regarded as the major cause of PD functional disability. Indeed, gait and balance problems may improve with dopaminergic treatment in most patients and they become unresponsive only at the very late stages of the disease. Moreover, several non-motor disturbances, including cognition and depression are often linked to oscillation of dopamine concentrations, and are frequently relieved by treatments providing continuous dopaminergic delivery. Finally, drug trials testing non-dopaminergic treatments for motor and non-motor symptoms of PD provided so far disappointing results. Despite the impressive advances of PD therapeutic strategy, we think there is still need for safe, non-invasive and easily manageable dopaminergic treatments able to provide constant dopamine receptor stimulation and ensure a more stable control of dopamine responsive motor and non-motor symptoms at any stage of the disease.     

Pulsatile or continuous dopaminomimetic strategies in Parkinson's disease

Levodopa is the most effective treatment for Parkinson's disease (PD) for both motor and non-motor control. Pulsatile levodopa administration likely contributes to the development of motor fluctuations and dyskinesia after a few years. All studies comparing levodopa versus dopamine agonist early therapy indicate that initiation with agonists is associated with a reduced risk of motor complications - in particular, dyskinesias - possibly because agonists' longer half-lives provide continuous dopaminergic delivery. Indeed, this therapeutic strategy may delay the emergence of motor fluctuations and dyskinesia which is essential to maintaining satisfactory quality of life. In advanced disease various levodopa-based strategies may be tried to control motor complications, such as dose fragmentation (smaller, more frequent dosing) or the use of orally administered, liquid levodopa formulations that may reduce off-time intervals or facilitate absorption. More recently introduced, continuous levodopa delivery by duodenal infusion (but also apomorphine infusion) may represent a more effective approach to treat motor complications in advanced PD, and its effect can be perceived by improvement both in clinical scales as well as in health-related items. Infusion therapies may reverse motor complications in complicated patients with significant benefit on quality of life.     

Beating a dead horse: dopamine and Parkinson disease

Our collective thinking about Parkinson disease (PD) has been heavily influenced by the dramatic response to dopamine replacement therapy. For progress to continue, however, we need to take a broad view of this disorder, which includes recognition of the following. First, substantial evidence now indicates that dopamine oxidation is unlikely to substantially contribute to the pathogenesis of PD. Second, levodopa therapy is not associated with neurotoxicity. Third, the first neurons affected in PD are nondopaminergic; the substantia nigra and other dopaminergic nuclei are affected only later in the course. Thus, PD is much more than degeneration of the dopaminergic nigrostriatal system. Fourth, in the current era, most of the disability of advancing PD is from involvement of nondopaminergic systems, including levodopa-refractory motor symptoms, dementia, and dysautonomia. Motor complications associated with levodopa therapy can be problematic, but they can be controlled in most, using available medications and deep brain stimulation surgery. We have reached the point of diminishing therapeutic returns with drugs acting on dopamine systems; more dopaminergic medications will provide only modest incremental benefit over current therapies. Finally, the benefits from transplantation surgeries aimed at restoring dopaminergic neurotransmission will be limited because later-stage PD disability comes from nondopaminergic substrates. Scale.     

Continuous dopaminergic delivery in Parkinson’s disease

Motor fluctuations and dyskinesias occur in the majority of patients with Parkinson’s disease (PD) and are likely to result from changes in dopamine production, storage and release, occurring as consequences of the nigrostriatal degenerative process. All studies comparing levodopa versus dopamine agonist early therapy indicate that initiation with agonists is associated with a reduced risk of motor complications —in particular, dyskinesias— possibly because agonists’ longer half-lives provide continuous dopaminergic delivery. In advanced PD patients, switching from a pulsatile to continuous dopaminergic delivery may widen patients’ therapeutic window. Currently, this can be accomplished only with subcutaneous apomorphine or duodenal levodopa infusions. Apomorphine is a highly soluble agonist whose effect is similar to dopamine. Conversely, replacing whole oral therapy with levodopa infusion bypasses gastric emptying and avoids peaks and troughs in plasma by releasing levodopa in the duodenum/jejunum.

     

A new look at levodopa based on the ELLDOPA study

Levodopa has been the gold standard for Parkinson's disease (PD) therapy since it was successfully introduced in 1967. But in the years since then, after recognizing that levodopa often leads to the motor complications of wearing-off and dyskinesias, there have been debates among clinicians as to when levodopa therapy should be started. Delaying therapy was advocated for the purpose of delaying the development of these motor complications. This became more popular as the dopamine agonists became available. Although less potent than levodopa in ameliorating the symptoms of PD, they were much less likely to produce the unwanted motor complications, even though they had their own adverse effects. When it was recognized that dopamine, itself, might be a factor leading to the death of dopaminergic neurons through its contributing to the formation of oxyradicals, a new concern arose, namely that levodopa, through its conversion to brain dopamine, might add to the existing oxidative stress and possibly enhance neurodegeneration of dopaminergic neurons. Though widely debated and without definite evidence, this possibility was sufficient to make some clinicians have further reason to delay the start of levodopa therapy. The ELLDOPA study was created to test this hypothesis. The clinical component of the study failed to find an enhancement of PD symptoms after levodopa was withdrawn following 40 weeks of levodopa therapy. Rather, the clinical results indicated that the symptoms had progressed much less than placebo, and in a dose-response manner. This suggests that levodopa may actually have neuroprotective properties. The uncertainty that a 2-week withdrawal of levodopa may not have entirely eliminated its symptomatic benefit and the discordant results of the neuroimaging component of the ELLDOPA study have created even more uncertainty that levodopa is neuroprotective. A survey of neurologists who treat PD patients showed that the vast majority of these clinicians do not believe levodopa is neuroprotective, and they remain concerned about the drug's likelihood of inducing motor complications. Thus, the ELLDOPA study failed to change the treating pattern of PD, and the clinicians require more convincing evidence of either neuroprotection or neurotoxicity of levodopa before they would alter their treatment approach.     

Medication impairs probabilistic classification learning in Parkinson's disease

In Parkinson's disease (PD), it is possible that tonic increase of dopamine associated with levodopa medication overshadows phasic release of dopamine, which is essential for learning. Thus while the motor symptoms of PD are improved with levodopa medication, learning would be disrupted. To test this hypothesis, we investigated the effect of levodopa medication on learning on the weather prediction task (WPT), which involves probabilistic classification learning. 11 PD patients and 13 matched controls completed 200 trials of the WPT, with the patients either on or off their usual levodopa medication. Consistent with prior studies, when PD patients were assessed on medication, overall WPT performance was significantly worse than controls. However, when these patients were studied following withdrawal from medication, overall performance was equivalent to controls, and significantly better than when on medication. The significant deterioration of learning on the WPT in PD patients when on compared to off medication supports the proposal that tonic increase of dopamine with dopaminergic medication masks phasic changes in dopamine release essential for learning. These results highlight the need for careful ‘titration’ of dopaminergic medication to produce the desired improvement of the motor symptoms without the associated detrimental effects on cognition and learning.     

D1 and functionally selective dopamine agonists as neuroprotective agents in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that results in major motor disturbances due primarily to loss of midbrain dopamine neurons. The mainstream treatment has been dopaminergic replacement therapy aimed at symptomatic relief, with the gold standard drug being the dopamine precursor levodopa. The general dogma has been that levodopa works primarily by indirectly activating the D(2) family of dopamine receptors. Recently, a number of direct dopamine agonists that target the D(2) and D(3) dopamine receptors have been used as dopaminergic replacement strategies. Although these direct D(2) and D(3) drugs cause only modest improvement in motor function compared to levodopa, they can delay the initiation of levodopa and can act synergistically with levodopa. In addition, they can delay the onset of levodopa-related motor complications. Recent imaging data also suggest that they may have neuroprotective effects. Whereas D(2)/D(3) agonists have received much attention as several drugs are available for clinical trials and usage, there has been a large body of data showing that the D(1) receptor actually may play a larger role in restoration of normal motor function. This review examines the current use of dopamine D(2)/D(3) agonists in treatment of PD and their potential for providing neuroprotection. Furthermore, we also examine the potential that D(1) agonists might have in neuroprotective actions in the disease progression.     

Levodopa treatment and dendritic spine pathology

Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective treatment for the motor symptoms of PD. However, chronic oral levodopa treatment can lead to various motor and nonmotor complications because of nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission. Recent studies using rodent models have reported dendritic spine head enlargement in the caudate‐putamen, nucleus accumbens, primary motor cortex, and prefrontal cortex in cases where chronic levodopa treatment following dopaminergic denervation induced dyskinesia‐like abnormal involuntary movement. Hypertrophy of spines results from insertion of alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropanoic acid receptors into the postsynaptic membrane. Such spine enlargement indicates hypersensitivity of the synapse to excitatory inputs and is compatible with a lack of depotentiation, which is an electrophysiological hallmark of levodopa‐induced dyskinesia found in the corticostriatal synapses of dyskinetic animals and the motor cortex of dyskinetic PD patients. This synaptic plasticity may be one of the mechanisms underlying the priming of levodopa‐induced complications such as levodopa‐induced dyskinesia and dopamine dysregulation syndrome. Drugs that could potentially prevent spine enlargement, such as calcium channel blockers, N‐methyl‐D‐aspartate receptor antagonists, alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropanoic acid receptor antagonists, and metabotropic glutamate receptor antagonists, are candidates for treatment of levodopa‐induced complications in PD. © 2017 International Parkinson and Movement Disorder Society     

Optimizing long-term therapy for Parkinson disease: levodopa, dopamine agonists, and treatment-associated dyskinesia

The treatment of Parkinson disease (PD) involves pharmacological treatment, often with levodopa or dopamine agonists, to restore the dopaminergic deficit associated with parkinsonian symptoms. Either agent provides symptom relief that becomes less effective in the course of PD, and switching or combining these agents or adding other therapies becomes necessary for symptom control. In an effort to delay the development of motor complications, dopamine agonists are often used in the initial treatment of PD. However, control of PD symptoms is superior with levodopa. Moreover, dopamine agonists are less well tolerated overall and are associated with a number of rare but serious adverse effects. In the long-term management of PD, treatment-associated dyskinesia often becomes sufficiently troublesome as to compromise the effective dosing of antiparkinsonian medication. More effective strategies for managing dyskinesia are needed.     

Therapeutic strategies to prevent motor complications in Parkinson's disease

Dopaminergic treatment of Parkinson's disease (PD) leads to significant improvement in Parkinsonian features; however, the treatment response is hampered by the appearance of motor complications, including dyskinesias and motor fluctuations. These motor complications have a significant negative impact on quality-of-life. Therapeutic strategies using different types and timing of dopaminergic therapy may influence the emergence of motor complications. While sustained release preparations of levodopa have not shown benefit over immediate release preparations, the early combination of a dopamine agonist with levodopa appears to reduce the onset of motor fluctuations. An even larger body of evidence has found that initiating treatment with a dopamine receptor agonist (as compared to immediate release levodopa) is associated with a reduction in motor fluctuations, particularly dyskinesias. These data have led to evidence-based medicine evaluations indicating that the use of dopamine agonists is efficacious and clinically useful for the prevention of motor complications.     

Levodopa in the treatment of Parkinson's disease

The predominant motor features of Parkinson's disease (PD) are caused by degeneration of dopaminergic neurones and can be reversed in part or whole by dopamine replacement or augmentation strategies. Physicians have most experience with the use of levodopa, which remains the most potent oral dopaminergic treatment for PD. There are reservations about the long-term use of levodopa, most particularly in the context of its propensity to induce motor fluctuations and dyskinesias. Strategies exist to delay or diminish these complications, but the physician must lay the basis for these in the selection of drugs for early treatment and the sequence of drugs introduced subsequently. Levodopa efficacy and duration of effect may be enhanced by combination with a catechol- O -methyl transferase inhibitor. Maintaining good motor function and quality of life remain the primary goals of therapy and the principle that treatment must be tailored to the individual patient's needs is paramount.     

Are we listening to everything the PARK genes are telling us?

The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of dopamine neurons in the substantia nigra has been known for the last 50. These long-established facts have fueled a broadly held expectation that degenerating dopaminergic neurons alone hold the key to understanding and curing PD. This prevalent expectation is at odds with the observation that many nonmotor symptoms, including depression and cognitive inflexibility among others, can appear years earlier than the overt dopaminergic neuron degeneration that drives motor abnormalities and are not improved by levodopa treatment. Thus, preserving or rescuing dopamine neuron health and function is of paramount importance, but this alone fails to capture the underlying neurobiology of earlier-appearing nonmotor symptoms. Insight into the complete landscape of disease-related abnormalities and the context in which they arise can be gleaned from a more comprehensive consideration of the PARK genes that are known to cause PD. Here, we make the case that a full incorporation of research showing when and where PARK genes are expressed as well as the impact of gene mutation on function throughout life, in tandem with research studying how dopaminergic neuron degeneration begins, is essential for a full understanding of the multi-dimensional etiology of PD. A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation and help to identify mechanisms conferring the resilience or susceptibility of some cells and systems over others.     

Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease

OBJECTIVES: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa. METHODS: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. RESULTS: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. CONCLUSIONS: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.     

Rasagiline in treatment of Parkinson's disease

Rasagiline (N-propargyl-1 (R)-aminoindan) is a novel propargylamine, irreversible, selective monoamine oxidase inhibitor for treatment of Parkinson's disease (PD), a progressive condition associated with degeneration of dopaminergic neurons in the substantia nigra. Rasagiline inhibits striatal dopamine metabolism, thereby providing relief from motor symptoms of PD. It may be dosed once daily and, unlike selegiline, it is metabolized to non-amphetamine compounds. In a large clinical trial, rasagiline has proved effective, safe, and well tolerated in early PD as monotherapy. In two phase III clinical trials in advanced PD with motor fluctuations, rasagiline as an adjunct to levodopa significantly decreases "off" time. In animal models of PD, data supports a neuroprotective effect of rasagiline, and its active metabolite aminoindan. Analysis of delayed-start clinical trial suggests the potential for disease modification, and further trials are examining this effect.     

Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson's disease: long-term results

Fluctuations in motor disability and dyskinesias are the major problem in the long-term treatment of Parkinson's disease (PD). Many authors and ourselves have shown that by giving patients a continuous infusion of levodopa it is possible to control motor fluctuations. Levodopa can be administered continuously only be intravenous, intragastric or intrajejunal delivery. Continuous dopaminergic stimulation an be achieved more easily by infusing dopamine agonists subcutaneously. Apomorphine is a potent water-soluble dopamine receptor agonist that has been shown to successfully control motor fluctuation when subcutaneously infused in complicated parkinsonian patients. We report the clinical data of 30 PD patients having at least five years of treatment with subcutaneous continuous apomorphine infusion.     

Brain grafting may reverse loss of responsiveness to levodopa therapy in Parkinson's disease

Loss of efficacy and response fluctuations develop in many patients with Parkinson's disease after long-term levodopa therapy. This may be due in part to near-total degeneration of the surviving nigrostriatal dopaminergic neurons during disease progression, with massive decreases in the capacity of the striatum to form and store dopamine from exogenous levodopa. It was recently suggested that intracerebral grafting of fetal nigral or adrenal chromaffin cells may be beneficial in advanced Parkinson's disease by reestablishing spontaneous dopaminergic neurotransmission or by secretion of trophic factors that promote sprouting of residual dopaminergic nerve-terminals. It is now hypothesized that intrastriatal transplantation of such cellular elements that contain the enzyme dopa decarboxylase and dopamine storage sites may significantly increase synthesis, storage, and release of dopamine from exogenous levodopa. It may therefore reverse loss of responsiveness and restore the initial smooth and stable beneficial effect of levodopa therapy.     

Pharmacokinetic and pharmacodynamic considerations in management of motor response fluctuations in Parkinson's disease

Recent advances in the understanding of the pharmacokinetics of levodopa and other anti-Parkinson agents have brought about the development of rational approaches to the management of levodopa-related fluctuations in motor performance that plague the majority of patients with advanced PD. The rapid systemic clearance of levodopa underlies the "short duration" response to the drug, which is progressively unmasked as PD progresses and central dopamine synthetic and storage capacity can no longer buffer fluctuations in plasma levodopa levels. Dyskinesias may be considered a secondary pharmacodynamic consequence of such pharmacokinetically induced oscillations in brain dopamine levels. Therapeutic approaches aimed at stabilizing brain dopaminergic activity include the use of slowly releasing galenic formulations of levodopa, synthetic dopamine agonists of long-lasting biologic activity, and drugs such as deprenyl that act as "dopamine extenders." It remains to be seen whether early use of such treatment approaches will reduce the prevalence of motor response fluctuations, which are one of the most disabling complications of long-term treatment of PD.     

Treatment of motor symptoms in advanced Parkinson's disease: a practical approach

Patients with advanced Parkinson's disease (PD) are known to develop motor complications after a few years of levodopa (l-dopa) therapy. Motor fluctuations develop with increasing severity of the disease, owing to loss of dopaminergic neurons and loss of the buffering capacity of the neurons to fluctuating dopamine levels. Dyskinesias develop as a result of pulsatile stimulation of the receptors and alterations in neuronal firing patterns. l-dopa remains the gold standard medication for the treatment of patients with advanced PD. However, once motor complications on l-dopa therapy emerge, clinicians may add on other classes of antiparkinsonian drugs such as dopamine agonists, catechol-O-methyl transferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs). The individualisation of the treatment seems to be the key for the best approach of advanced PD patients. The present review provides the most important current clinical data in the pharmacological treatment of motor symptoms in advanced PD and provides the clinician a simple algorithm in order to determine the best suitable treatment to advanced parkinsonian patients.