European Journal of Neurology

Volume 15 Issue 1 Page 6-15, January 2008

REVIEW ARTICLE
Constant dopaminergic stimulation by transdermal delivery of dopaminergic drugs: a new treatment paradigm in Parkinson's disease

* M. Steiger

*
Walton Centre for Neurology and Neurosurgery, NHS Trust, Liverpool, UK

ABSTRACT:

Current dopaminergic therapies for the treatment of Parkinson's disease are associated with the development of long-term motor complications. Abnormal pulsatile stimulation of dopamine receptors is thought to underlie the development of motor complications. There is thus a need for therapies that mimic the normal physiological state more closely by resulting in constant dopaminergic stimulation (CDS). Several studies support the hypothesis that CDS can reverse levodopa-induced motor complications. Other potential benefits of CDS include alleviating nocturnal disturbances, minimizing daytime sleepiness, avoiding priming for motor fluctuations and dyskinesia, preventing the development of gastrointestinal dysfunction and reducing the risk of developing psychosis or behavioural disturbances. Continuous infusion of dopaminergic therapies is impractical for the routine treatment of large numbers of patients. Although catechol-O-methyltransferase inhibitors or sustained-release preparations of levodopa may be beneficial, they do not entirely eliminate pulsatile stimulation of dopamine receptors. A new dopamine agonist (rotigotine), delivered over 24 h by a once-daily transdermal patch, has been investigated in several clinical trials. Continuous delivery of rotigotine has been shown to provide ‘true’ CDS in animal models. The potential of true CDS therapy to prevent or reduce long-term motor and non-motor complications requires investigation in appropriately designed clinical trials.

This review is based on an extensive literature search of the Medline and Embase databases, performed during May 2006 and covering the years 1975–2006. Additional articles were obtained from the reference lists of retrieved articles. Peer-reviewed abstracts from recent scientific meetings were also considered for inclusion.

Parkinson's disease (PD) is one of the most common neurological disorders in elderly people. Estimates of the prevalence of PD vary across countries and studies [1], but analyses of these studies indicate that the prevalence in people aged 65 years or over is approximately 1.6% [2]. The prevalence of PD increases with age, rising from 0.6% at 60–64 years to 2.7% at 75–79 years [2]. Given that the average age in the developed world is rising [3], it is clear that PD represents an increasing health burden.

The cause of PD is still unknown, but it may involve both genetic and environmental factors [4]. PD involves progressive loss of dopaminergic cells and other neurons involved in serotonergic, noradrenergic and cholinergic transmission, initially at the level of brainstem, but progressively including subcortical and later cortical regions [5,6]. The resulting neurochemical imbalance is responsible for the characteristic signs and symptoms of this multisystem disorder. Motor symptoms begin to manifest in parallel with the pathological changes in the substantia nigra [5].

The diagnostic criteria of PD are bradykinesia/hypokinesia and at least one of: muscle rigidity, tremor at rest or postural instability [7]. Episodic gait disturbances in the form of freezing or festination can also be regarded as a cardinal motor sign of parkinsonism [8]. Other non-motor symptoms associated with PD include affective disturbances, cognitive decline, fatigue, sleep disorders, pain and autonomic symptoms, such as constipation, erectile dysfunction and urgency of micturition [9].

Parkinson's disease is associated with a significant socioeconomic costs, which increases markedly with disease progression [10]. The substantial increase in costs with increasing severity of PD is driven to a large extent by the onset of motor complications [11], as well as factors contributing to the institutionalization, such as the appearance of psychiatric symptoms [12]. In the absence of proven disease-modifying therapies, there is a need for therapies that can reduce the long-term complications, both motor and non-motor, which are associated with the current treatment options for PD.

Limitations of current therapies

Levodopa is the benchmark for the symptomatic treatment of PD. Although levodopa is a highly effective treatment for motor symptoms [13], motor complications develop with time. Typically, these occur after 4–6 years of therapy, and affect approximately half of all patients [14,15]. Motor complications include both choreiform and dystonic movements (dyskinesia), which can range from being mild and unnoticed to very disabling, and motor response fluctuations (changes between akinetic and mobile states). In addition to motor response fluctuations, some patients also develop fluctuations in mood [16], alertness [17], pain [18,19] and degree of fatigue [19]. The development of dopaminergic therapy-associated motor and non-motor complications depends on the extent of disease progression [15,20], age at disease onset [21,22] and on both the total dose and duration of dopaminergic treatment [15,21]. Levodopa-related motor response complications represent an important source of disability for patients with PD, and can be difficult to manage.

The clinical approach to managing such complications can be a combination of low and multiple doses of levodopa, with or without a long-acting dopamine agonist [23,24], as well as functional neurosurgery [25]. Dopamine agonists cause fewer and milder long-term motor complications than levodopa, but result in smaller improvements in motor performance [26–29].

Continuous dopaminergic stimulation


Under normal circumstances, nigral neurons fire continuously, exposing striatal dopamine receptors to relatively constant levels of dopamine [30], thus providing constant dopaminergic stimulation (CDS). The firing rate of dopaminergic neurons increases in response to novel stimuli or in anticipation of reward, but re-uptake into pre-synaptic terminals ensures that extracellular concentrations of dopamine remains constant [30]. In PD, there is a loss of the nigral neurons and their striatal terminals that normally store and regulate the release of dopamine.

Advancing disease results in fewer remaining striatal dopamine terminals and consequently decreased capacity to buffer fluctuations in dopamine levels. Thus, disease severity contributes to pulsatile stimulation of dopamine receptors. Abnormal pulsatile stimulation of striatal dopamine receptors is thought to lead to dysregulation of genes and proteins in downstream neurons and consequent alterations in neuronal firing patterns that are thought to underlie the development of motor complications [31–36].

Parkinson's disease patients typically develop dyskinesia several years after starting levodopa therapy. However, dyskinesia develops within months of starting levodopa therapy in subgroups of patients with young-onset PD or with advanced disease at the time of initial diagnosis, and in subjects with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, who have a more-severe loss of nigral neurons [15,20,22,37]. Studies in animal models support the hypothesis that a greater loss of dopaminergic cells in the substantia nigra correlates with more severe dopaminergic therapy-related dykinesias.

For example, dyskinesia was found to develop within weeks of initiating levodopa therapy in MPTP-lesioned monkeys with >90% loss of nigral neurons [38]. Similarly, motor fluctuations occurred within a week of levodopa therapy in 6-hydroxydopamine-lesioned rats with >95% loss of dopaminergic neurons [39].

In addition to an increased sensitivity to fluctuating dopamine levels because of loss of nigral neurons, exposure to variable levels of a dopaminergic agent because of a short half-life or erratic absorption from the gastrointestinal (GI) tract [40] may also contribute to the development of motor complications.

These hypotheses are supported by observations in animal models. For example, levodopa and short-acting dopamine agonists were found to induce severe dyskinesia in MPTP-lesioned monkeys [38,41–43], whereas long-acting dopamine agonists did not [38,44,45]. In addition, short-acting dopamine agonists induced dyskinesia in MPTP-lesioned monkeys when administered intermittently, but not when administered continuously by infusion pump [46].

In interpreting these studies, it is important to be aware that the current animal models do not fully reproduce the pathology of PD [47], and that the equivalent doses of dopaminergic agents used in clinical practice are often relatively low [48]. Studies in patients with advanced PD have shown that continuous infusion of levodopa or dopamine agonists is associated with a decrease in the severity or frequency of motor fluctuations and dyskinesia than therapies of shorter half-life [49–51].

Dopamine agonists generally have a longer half-life than levodopa (Table 1) and, therefore, assuming that constant plasma levels lead to continuous receptor stimulation, do not expose receptors to rapidly fluctuating levels of stimulation. In addition, dopamine agonists act directly on dopamine receptors and do not require dopaminergic nerve terminals for their action, whereas levodopa has to be converted to dopamine in the dopaminergic terminals. Clinical trials in patients with PD have demonstrated that the risk of inducing dyskinesia is reduced if therapy is initiated with a relatively long-acting dopamine agonist compared with levodopa [26,27,52].

It is unknown whether dyskinesia and motor response fluctuations are caused by a common pathophysiological mechanism, or whether different underlying processes are involved. However, findings from a recent study of patients on levodopa monotherapy suggests that dyskinesia predicts the onset of motor response fluctuations, and that these motor complications may therefore share a common pathophysiological pathway [53]. There is a need for dopaminergic treatments that provide non-pulsatile CDS and can thus mimic the normal physiological state more closely.
Benefits of CDS

Benefits of CDS

Established benefits

Several studies support the hypothesis that CDS can reverse motor complications. For example, a 4-year trial in 40 patients showed that continuous infusion of lisuride significantly reduced motor fluctuations and dyskinesia compared with standard dopaminergic therapy [50]. Similarly, a random crossover trial in 12 patients showed that intestinal infusion of levodopa was associated with a significant decrease in ‘off’ time and dyskinesia compared with sustained-release levodopa [49].

There are no large, double-blind, placebo-controlled trials of CDS via continuous infusion of dopaminergic agents in patients with advanced PD and motor complications. However, many small-scale studies and clinical experience have confirmed that continuous subcutaneous infusions of apomorphine are beneficial in reducing motor fluctuations and dyskinesia [54–59]. For example, a study of 12 PD patients with ‘on–off’ fluctuations and severe dyskinesia showed that continuous subcutaneous apomorphine infusion therapy resulted in a significant improvement in dyskinesia, accompanied by a reduction in dyskinesia during dopaminergic challenge tests [57]. Studies of CDS via continuous infusion have only been performed in patients with advanced PD who already have motor complications; no studies to date have demonstrated whether CDS can prevent the onset of motor complications.

Constant dopaminergic stimulation may also have beneficial effects on sleep. Nocturnal disturbances are extremely common in patients with PD, and can include PD-related motor symptoms, such as nocturnal akinesia and early-morning dystonia, as well as other sleep disorders, such as sleep fragmentation, restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) [60].

Several studies have shown that dopaminergic agents with a longer duration of action can reduce nocturnal and early-morning motor fluctuations. For example, the long-acting dopamine agonist cabergoline provided more-effective relief of nocturnal painful dystonia and akinesia than controlled-release levodopa [61], and was more effective than standard levodopa for relief of morning akinesia and early-morning dystonia [27]. Cabergoline has also been shown to have beneficial effects on PLMS [62]. A study of six parkinsonian patients with nocturnal disabilities showed that nocturnal subcutaneous infusion of apomorphine significantly reduced nocturnal awakenings, ‘off’ periods, pain, dystonia and nocturia, compared with conventional therapy [63]. In patients with RLS, nocturnal apomorphine infusion reduced nocturnal discomfort and leg movements, and significantly improved pain and spasm scores [63]. The results of a study in 63 patients with RLS showed that continuous delivery of the dopamine agonist rotigotine over 24 h by means of a transdermal patch significantly improved both nighttime and daytime RLS symptoms [64]. Overall, the findings of the studies described above support the hypothesis that nocturnal disturbances can arise as a consequence of inadequate nighttime dopaminergic stimulation, which could potentially be alleviated by CDS.

In addition to disturbed sleep, fluctuating levels of dopamine receptor stimulation may also contribute to the daytime sleepiness that is frequently seen in patients with PD [65]. It was shown that replacing the currently used dopamine agonist with an equivalent dose of a long-acting dopamine agonist (cabergoline) reduced daytime sleepiness by 70% during a 3-month study [65], which suggests that more-continuous dopaminergic stimulation might be beneficial. One note of caution is that dopamine agonists have been associated with sleep attacks in a small proportion (5–7%) of patients [66,67].

It is not known whether the incidence of sleep attacks would be reduced for dopamine agonists delivered in a more-continuous fashion. Further studies are required to determine whether CDS using dopamine agonists can reduce daytime sleepiness, as well as alleviating the nocturnal disturbances that affect many patients with PD.

Potential modification of disease course

As well as alleviating dyskinesia in patients who have been receiving dopaminergic therapy, the use of non-pulsatile CDS as initial therapy may have the potential to prevent priming for motor fluctuations and dyskinesia. In support of this hypothesis, it has been shown that, whereas bolus administration of either levodopa or the dopamine agonist rotigotine induces sensitization of locomotor activity in a rat model of dyskinesia, continuous administration of rotigotine does not induce dyskinesia in this model [68]. It is believed that levodopa induces dyskinesia as a consequence of persistent or permanent alteration of basal ganglia function, which leads to the appearance of involuntary movements upon dopamine receptor stimulation [35,69].

A more physiological stimulation of dopamine receptors from therapies that provide CDS may prevent the alteration in basal ganglia function, and thus prevent priming for dyskinesia. It has also been shown that chronic levodopa therapy affects the function of specific dopaminergic pathways before dyskinesia has developed [70], suggesting that early use of CDS would be beneficial.

Gastrointestinal dysfunction is very common in PD [71], and impaired GI dysfunction with subsequent erratic absorption of levodopa has been proposed to contribute to the development of motor response complications, such as ‘delayed-on’ and ‘no-on’ [40]. In addition to the disease process in the GI tract, it is thought that levodopa treatment may also contribute to impaired GI function [40]. Stimulation of dopamine receptors from trapped levodopa within the stomach may further retard gastric emptying [72] and thereby augment the fluctuating levels of levodopa. Furthermore, in parallel to the alteration of basal ganglia function that is proposed to be responsible for dyskinesia, it is thought that modification of dorsal motor vagal nucleus (DMVN) function may contribute to GI dysfunction [40]. CDS may have the potential to prevent the modification of DMVN function, particularly if delivered via a non-oral route. Further studies are warranted to investigate whether CDS has any effect on the risk of developing GI dysfunction.

Psychosis is one of the most disabling non-motor complications of PD, and occurs in up to 40% of PD patients treated chronically with antiparkinsonian drugs [73,74]. It has been suggested that pulsatile stimulation of dopaminergic receptors in association with the progressive degeneration of neuronal pathways leads to perturbations in limbic and frontal cortex neurotransmitter pathways that result in the development of psychosis [75]. Therefore, avoiding pulsatile stimulation through the use of CDS might be expected to reduce the risk of developing psychosis. This hypothesis needs to be tested in clinical trials.

There has been recent concern that dopaminergic therapy may increase the incidence of risk-taking behaviour, such as gambling, and obsessions with food, shopping and sexual activities in patients with PD [76]. Because comorbid gambling behaviour begins after the onset of PD and worsens with dopaminergic therapy, and because it appears more often in the ‘on’ periods of patients with motor fluctuations, it has been suggested that it may be due to abnormal dopaminergic tone [77]. It remains to be seen whether CDS could reduce the risk of pathological gambling and other behaviour disturbances associated with the dopamine dysregulation syndrome.

It is not known whether CDS might also slow down the development of other features of the later stages of the disease, such as problems of speech, pain, gait hesitation and freezing. The potential benefits of CDS need to be assessed in long-term prospective studies looking at specific aspects of advanced PD, such as sleep, behavioural problems, psychosis and gait abnormalities, as primary outcomes.
Therapeutic strategies to achieve non-pulsatile CDS

Continuous infusion

Studies with continuous infusion of levodopa or dopamine agonists support the hypothesis that continuous stimulation of dopamine receptors can lead to the improvement in motor complications [49–51,54–58,78]. These studies have shown that continuous infusion of levodopa or dopamine agonists reduces the severity, frequency and duration of dyskinesia and motor fluctuations, as well as reducing ‘off’ time (Table 2). The beneficial effects of continuous levodopa infusion on motor fluctuations and dyskinesia may arise both from bypassing erratic gastric emptying (and thus giving greater and more-constant bioavailability) and from central effects at the level of the dopamine receptors.

These studies have also demonstrated that long-term CDS from continuous infusion of dopamine agonists is sustained and is not associated with tolerance to the beneficial effects of CDS [54,59]. However, although continuous infusion provides evidence to support the potential benefit of CDS, it is expensive and impractical for the routine treatment of large numbers of patients. Furthermore, there are no data at the present time to support a protective or preventative effect of continuous infusion on the development of dyskinesia or motor response fluctuations. Large, prospective, double-blind, placebo-controlled trials of CDS via continuous infusion are needed.
Increased frequency of dosing


Another approach that has recently been adopted by some clinicians is to increase the frequency of levodopa dosing. However, although this approach may provide more-continuous stimulation, it is inconvenient for patients and/or carers. It is well known that compliance decreases as dosage frequency increases [79]. Furthermore, the sustained long-duration response (LDR) to levodopa is dependent on the amount of the single doses of the drug, and a regimen of small divided doses may not achieve a sustained LDR [80]. It has been suggested that maintaining the LDR is important to prevent the appearance of motor fluctuations [81].
Sustained-release formulations of levodopa


A relatively continuous stimulation of dopamine receptors could be achieved by using sustained-release formulations of levodopa. Sustained-release formulations of levodopa have a half-life of 3–6 h, compared with 1–1.5 h for standard formulations [82–84]. However, sustained-release formulations of levodopa have reduced bioavailability (60–70% of that of the standard formulations) [82–84]. Sustained-release formulations of levodopa have been shown to be as effective as standard levodopa in controlling the symptoms of PD [85,86]. However, two randomized, controlled, double-blind trials showed no difference in the frequency or time to onset of dyskinesia between standard and sustained-release formulations of levodopa [85,86]. In the first of these trials, sustained- and immediate-release levodopa/benserazide (co-beneldopa) were compared, and no significant difference was shown in the incidence of dyskinesia, motor fluctuations, motor impairment or activities of daily living at 5 years [85]. Similarly, the second trial compared controlled- and immediate-release levodopa/carbidopa (co-careldopa), and no significant difference was shown in dyskinesia or motor fluctuations at 5 years, although the use of controlled-release levodopa/carbidopa did significantly improve activities of daily living compared with the immediate-release formulation [86]. These results may reflect the fact that, because of erratic gastric emptying and limited absorption time in the small intestine, even sustained-release formulations of levodopa are unable to provide stable plasma levodopa concentrations [49,86,87]. These data do not support the use of the existing modified-release levodopa preparations to delay the onset of levodopa treatment-related motor complications.
Catechol-O-methyltransferase inhibitors


In the presence of a dopa decarboxylase inhibitor, the main route for levodopa breakdown is metabolism to 3-O-methyldopa by catechol-O-methyltransferase (COMT) [88]. COMT inhibitors prevent the peripheral breakdown of levodopa/dopamine and result in a 30–50% increase in the half-life of levodopa [88]. In clinical practice, this results in a 30–60-min increase in the duration of response per dose [89]. COMT inhibitors are currently licensed for use as an adjunct to levodopa in advanced PD.

The COMT inhibitors tolcapone and entacapone have been shown to reduce ‘off’ time, reduce levodopa dose and modestly improve motor impairment and disability [89]. It has been proposed that more-continuous stimulation of dopamine receptors with frequent doses of entacapone and levodopa may reduce the occurrence of motor complications [90]. However, although COMT inhibitors reduce pulsatile stimulation of dopamine receptors, they do not eliminate it altogether. The ongoing STRIDE trial, a prospective, double-blind study comparing therapy with levodopa/carbidopa/entacapone to levodopa/carbidopa in patients with no prior levodopa experience, was designed to investigate the impact of more-continuous stimulation of dopamine receptors on motor complications [91], and may provide additional information to determine whether the degree of continuity of the stimulation is sufficient to prevent motor complications.
Transdermal drug delivery


Transdermal drug delivery may be another very practical method to achieve CDS. In addition to continuous drug delivery, transdermal formulations offer other advantages, such as convenience and absence of interactions with food. Transdermal drug delivery may also be particularly useful for patients with swallowing difficulties or fluctuating gastric emptying, and patients undergoing operations. Transdermal delivery of the dopamine agonist (+)-4-propyl-9-hydroxy-naphthoxazine showed initial promise, but the development was discontinued because it was not sufficiently effective as a monotherapy, in addition to concerns about its toxicity [92–94]. A transdermal preparation of the non-ergolinic dopamine agonist piribedil has also been investigated, but the development was halted because the size of patch that would be needed to deliver adequate amounts of the drug was impractical [95].

More recent research exploring the potential of transdermal delivery has focussed on a non-ergolinic, broad-spectrum dopamine agonist (rotigotine), delivered over 24 h by a once-daily transdermal patch. This formulation has recently been approved for clinical use, and has been investigated in several clinical trials. The rotigotine patch has been shown to significantly improve Unified Parkinson's Disease Rating Scale parts II and III scores when used in early-stage PD [96–98]. It has also been shown to increase ‘on time without troublesome dyskinesia’ when used as adjunctive therapy in patients with advanced PD [99,100]. Transdermal rotigotine was safe and well tolerated in these studies.

The continuous, uniform release of rotigotine from the transdermal delivery system has been demonstrated to give stable plasma drug levels over 24 h (Fig. 1; [101]), and animal models have shown that stable plasma levels of rotigotine translate into CDS [102]. In addition, it has also been shown that CDS by rotigotine has a very low propensity to induce dyskinesia in rats [68]. At the present time, there is a lack of prospective data to support a reduction in long-term motor response complications through the use of transdermal rotigotine, and the potential for preventing or reversing motor and/or non-motor complications through the use of CDS provided by transdermal rotigotine requires investigation in appropriately designed clinical trials.

When considering therapies to achieve CDS, it is important to realize that stable plasma levels do not necessarily translate into stable and continuous stimulation at the level of the dopamine receptor. To date, only one study in an animal model has demonstrated that stable plasma levels of a dopaminergic agent translate into CDS [102]. Furthermore, to mimic the actions of endogenous dopamine, CDS should involve all subtypes of dopamine receptors, but many dopaminergic agents have a receptor profile that is significantly different to dopamine [103].
Conclusion


There is a pressing need for PD therapies that provide non-pulsatile CDS. Studies of continuous infusion have demonstrated the potential value of CDS, but are not practical for widespread clinical use. Although strategies for extending the effects of levodopa, such as COMT inhibitors or sustained-release preparations of levodopa, may be beneficial, they do not entirely eliminate pulsatile stimulation of dopamine receptors. Transdermal drug delivery of rotigotine has been shown to provide ‘true’ CDS in animal models, and may have the potential to prevent or reduce long-term motor and non-motor complications.

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