Parkinson’s disease (PD) is a neurodegenerative disease characterised by a progressive degeneration of dopaminergic neurons and the subsequent reduction of striatal dopamine levels. Approximately 80% of the striatal nerve terminal and up to 60% of dopaminergic neurons in the substantia nigra must be lost before clinical symptoms of Parkinsonism become apparent. This is due to several compensatory mechanisms that include an increase in dopaminergic activity in the substantia nigra, down-regulation of dopamine transporters, and up-regulation of postsynaptic dopamine receptors in the striatum.1 The main aim of treatment for PD patients is to replace dopaminergic transmission at striatal synapses. 

In normal individuals, nigral neurons fire continuously, exposing striatal dopamine receptors to relatively constant levels of dopamine. In PD patients, periodic dosing and the short half-life of anti-parkinsonian drugs lead to more intermittent stimulation. Subsequently, abnormal pulsatile stimulation of striatal dopamine receptors may lead to dysregulation of genes and proteins in downstream neurons, and consequently, alterations in neuronal firing patterns. This may ultimately lead to motor complications and motor fluctuations. Typically, motor fluctuations and dyskinesias occur after four to six years of levodopa therapy, and affect approximately half of all patients.1 In the event the dose of levodopa is reduced, the clinical effect becomes insufficient and wears off quickly. On the other hand, if the dose is increased too much dyskinesia will develop. 

In order to prevent the development of motor complications a therapy that provides continuous dopaminergic stimulation (CDS) as observed in the normal state would be ideal. Different routes of administration of levodopa (L-dopa) and other dopaminergic drugs have been tried to achieve continuous dopaminergic stimulation.1

The rational for CDS
In normal individuals and under normal physiological conditions, dopamine neurons have relatively constant rates of tonic activity; however, increased firing in association with rewards and an unexpected stimulus does occur.2 The reuptake into pre-synaptic terminals ensures that extracellular concentrations of dopamine remain constant. As the disease advances, there will be fewer remaining striatal dopamine terminals and consequently decreased capacity to buffer fluctuations in dopamine levels. In addition to an increased sensitivity to fluctuating dopamine levels because of loss of nigral neurons, exposure to variable levels of a dopaminergic agent also contributes to fluctuations.3

In the early stages of oral levodopa treatment, PD patients experience extensive benefit from the drug. However, with long-term treatment; the duration of benefit after each dose becomes progressively shorter. The patients begin to experience fluctuations in motor response alternating between on-response with a good anti-Parkinson effect and off-response when levodopa does not adequately control motor symptoms. Fluctuations may also occur in non-motor symptoms such as psychological, autonomic and sensory symptoms.4
PD patients may develop dyskinesias several years after starting levodopa therapy and it typically occurs in association with high plasma concentrations of levodopa (peak-dose dyskinesia). Less commonly, dyskinesias can appear at or just before the onset of the ‘on’ response and then disappear during the ‘on’ period only to re-emerge as the ‘off’ period begins (diphasic dyskinesia). In addition, some patients may develop ‘off-period‘ dystonia accompanied by pain and sustained posturing (off-period dyskinesia).

A potential method for ameliorating motor fluctuations and dyskinesias is to supply dopamine in a continuous manner, thus avoiding fluctuations in dopamine levels associated with intermittent oral levodopa.5 In patients with advanced PD, continuous infusion of levodopa or a dopamine agonist has been shown to provide long-lasting and dramatic improvement of established motor complications.6 However, controlled-release formulations of levodopa have not been shown
to reduce the risk of motor complications compared with standard levodopa in double-blind controlled trials.7

Types of CDS
The options for levodopa continuous delivery system are via the intra-peritoneal or intra-duodenal routes, as levodopa is not sufficiently soluble to be administered via the transdermal route.8 Oral dopaminergic agonists with long half-lives and continuous transdermal or subcutaneous delivery of dopamine agonists are used to provide near continuous dopaminergic stimulation.

Levodopa therapy
The oral route is the main practical method of levodopa administration although other modes of administration have been investigated by several researchers. Intravenously administered levodopa is effective although relatively impractical for the chronic treatment of patients with PD.1 Levodopa is not sufficiently soluble to be administered via the transdermal route.8 A continuous delivery system via the intra-peritoneal or intra-duodenal routes could be an alternative.9 This would be especially true in patients who have delayed absorption of levodopa related to delayed and erratic gastric emptying, which contributes to the fluctuation in motor response.9 Infusion of carbidopa/levodopa (Duodopa®) or levodopa through a duodenal tube can facilitate increased mobility and functional ability in individuals with PD when conventional
drug therapy is unsuccessful in achieving
desired outcomes.10

Dopamine agonists
There are several delivery techniques of dopamine agonists that are in clinical use nowadays. Apomorphine, which relies on parenteral administration for maximum bioavailability, is administered via the subcutaneous route in routine clinical practice.11 However, it may be delivered via rectal, intranasal, sublingual and subcutaneous routes. Meanwhile, rotigotine and lisuride have both been formulated for delivery via skin patches.12 A prolonged-release oral ropinirole and pramipexole preparation is another method tried with success towards continuous dopaminergic stimulation.13

Deep brain stimulation
Deep brain stimulation (DBS) is quite an effective means of achieving CDS. However, DBS-related complications include dysarthria, eyelid apraxia and behavioural changes such as cognitive deterioration (40%), depression (8%), hypomania (4%), anxiety (2%) and occasional surgery-related (bleeding, infection) and hardware related complications (14%).14

Advantages of CDS
Experience with continuous infusions of levodopa and dopamine agonists has shown several potential advantages over the conventional intermittent dopaminergic stimulation with oral drugs.4 Continuous administration of levodopa may produce a constant supply of dopamine to the striatal dopaminergic receptors and mimic the state seen during normal tonic firing of dopaminergic neurons. This would avoid the fluctuations in dopamine levels that normally accompany intermittent oral levodopa dosing and thereby facilitate a more normal control of movement.5 This can be achieved through a continuous enteral infusion of a water-soluble form of levodopa. 

The main advantage of continuous duodenal infusion is that it provides continuous delivery of levodopa so that plasma concentrations of the drug can be kept near constant thus reducing motor complications. The beneficial effects of continuous levodopa infusion on motor fluctuations and dyskinesias arise because it bypasses erratic gastric emptying in Parkinson’s patients, which in turn increases the available dopa in the nervous system. This technique reduces both off periods and dyskinesias in clinical studies.15

Other methods used for achieving continuous dopaminergic stimulation with variable success include sustained-release levodopa, increased frequency of dosages, long-acting dopamine agonists, and catechol-O-methyl transferase inhibitors.

Subcutaneous apomorphine provides rapid, effective relief of off episodes associated with advanced PD.16 It is effective for rapid rescue from hypomobility, with a magnitude of motor improvement similar to that of levodopa.17 The effect begins within 20 minutes after dosing and lasts approximately 100 minutes. The use of continuous subcutaneous apomorphine is associated with marked reduction of dyskinesia.18 In general, continuous apomorphine can reduce the off time by more than 50% of cases and it markedly reduces pre-existing levodopa-induced dyskinesias.11

Rotigotine is uniquely formulated as a trans-dermal patch delivery system allowing for continuous, once-daily administration and better patient compliance. The trans-dermal formulation delivers rotigotine at a constant rate over 24 hours, providing a more continuous plasma concentration compared with oral formulations of dopamine agonists that are routinely administered several times a day.19 It is also useful in patients who have difficulties with oral medications because of dysphagia. Ropinirole 24-hour prolonged release provided continuous delivery of ropinirole over 24 hours, resulting in a smooth plasma concentration-time profile, and food had no significant effect on absorption.20 The advantages of this preparation are once-daily dosing, faster titration and more stable plasma levels.13 This drug was found to be a good adjunct therapy in patients with PD not optimally controlled with levodopa and can improve both motor and non-motor PD symptoms, while permitting a reduction in adjunctive levodopa dose.21

Clinical studies also showed that intravenous lisuride infusions provided a significant reduction in both motor fluctuations and dyskinesias compared with patients receiving standard dopaminergic therapies.22

Disadvantages of CDS
Direct duodenal-administered infusible L-dopa/carbidopa is effective for the management of refractory motor fluctuations in some PD patient populations. However, enteral infusions cannot mimic the function of the normal dopaminergic brain, and around-the-clock constant-rate administration carries the risk of causing refractory off periods associated with severe immobility and hyperpyrexia.23 Duodenal dopa administration has several disadvantages. First, a surgical procedure or percutaneous endoscopic gastrostomy is required for the placement of a small tube to the duodenum. Second, the accompanying pump may be cumbersome for some patients. Secondary effects may also occur, which include sporadic blockage of tubes, displacement of the inner tube, leakage at the tube connection, and local infections. Finally, high cost may be a limiting factor.1

Continuous subcutaneous apomorphine is associated with a clinically significant potential to cause nausea and orthostatic hypotension, and to cause psychiatric complications.17 However, in comparison with other dopamine agonists, continuous subcutaneous apomorphine is less likely to induce dopamine dysregulation syndrome.11 The most common side effects with rotigotine transdermal patch may include a high incidence of local reactions, nausea and somnolence. The rotigotine transdermal system was well tolerated at doses up to 6mg/24 hour.23 However, the main adverse effects (application site reactions, somnolence and nausea) were generally mild or moderate.24  

A significant number of patients treated with lisuride reported psychiatric side effects thus reducing its therapeutic usefulness.25 In addition, unusual coronary vasospasm was reported with intravenous use of this drug but some other clinicians have questioned cardiac side effects
of lisuride.26

Neuro-imaging and CDS
Several preclinical and clinical studies suggest that non-physiological pulsatile stimulation of striatal dopamine (DA) receptors induced by the use of short-acting oral levodopa preparations, which produce swinging levels of synaptic DA, may contribute to the onset of motor fluctuations and dyskinesias. By contrast, more continuous and less pulsatile forms of dopaminergic stimulation delivered by longer-acting oral dopamine agonists result in a more stable clinical response and delay the development of motor complications.5,6,27 Newer agents and drug-delivery systems, such as slow-release preparations, represent a significant step towards less pulsatile dopaminergic administration. However, their efficacy in providing steady brain levels of dopaminergic stimulation in the short and longer term has not yet been proved in patients.

Positron-emission Tomography (PET) has been extensively used in patients with PD to investigate the function of brain dopaminergic nerve terminals, providing useful information on the density of functioning nerve terminals in the striatum and DA storage capacity, the availability of post-synaptic dopaminergic receptors and changes in synaptic DA levels following behavioural and pharmacological challenges. However, current PET studies with antagonist tracers are unable to separate signal from high and low agonist affinity-receptor conformations and it is possible that the relative sub-populations are altered.27 Additionally, they do not exclude downstream neurotransmitter changes that can be induced depending on the kinetics of DA-receptor stimulation. There are no PET studies that have directly tested whether currently available drug approaches, which provide more sustained levodopa delivery, also provide stable and more prolonged synaptic levels of striatal DA along with a sustained motor response.28 However, it is clear that PET has a great potential in this specific research field and could provide valuable insight on the pharmacokinetics and pharmacodynamics of new agents and therapeutic strategies in PD.28

Conclusion
Pulsatile dopaminergic pharmacokinetics can contribute to the variable beneficial effects as well as to adverse effects of treatment of PD and may also cntribute to progression of motor side effects such as dyskinesias. CDS has therefore been considered an important therapeutic goal. 

Several treatment options are available to evoke CDS. Oral dopaminergic agonists with long half-lives and continuous transdermal or subcutaneous delivery of dopamine agonists are used to provide near continuous dopaminergic stimulation. Duodenal infusion of levodopa may produce a constant supply of dopamine to the striatal dopaminergic receptors and mimic the state seen during normal tonic firing of dopaminergic neurons. Thus it would avoid the fluctuations in dopamine levels that normally accompany intermittent oral levodopa dosing and thereby facilitate a more normal control of movement. However, enteral infusions cannot mimic the function of the normal dopaminergic brain; and around-the-clock constant-rate administration carries the risk of causing refractory off periods associated with severe immobility and hyperpyrexia.

Conflict of interest: none declared

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