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Treatment of Parkinson's disease aims to replace dopaminergic transmission at striatal synapses. In the normal state, nigral neurons fire continuously, exposing striatal dopamine receptors to relatively constant levels of dopamine. In the disease state, periodic dosing and the short half-life of antiparkinsonian drugs leads to more intermittent stimulation. 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. In order to prevent the development of motor complications a therapy that provides continuous dopaminergic stimulation as observed in the normal state would be ideal. Different routes of administration of levodopa and other dopaminergic drugs have been tried to achieve continuous dopaminergic stimulation (CDS). This review discusses the various methods available to achieve this goal with particular emphasis on duodenal dopa administration.
Levodopa is the time-tested drug for the symptomatic treatment of Parkinson's disease and is highly effective in the treatment of motor symptoms. Patients on long-term levodopa therapy are prone to develop motor fluctuations and dyskinesias [Fahn et al. 2004]. Typically, these occur after 4 to 6 years of therapy, and affect approximately half of all patients [Ahlskog and Muenter, 2001]. These motor fluctuations are due to the dose-related pulsatile stimulation of dopaminergic receptors. In the event the dose of levodopa is reduced, the clinical effect becomes insufficient and wears off quickly. If the dose is increased too much dyskinesia will develop.
Several dopamine agonists have been shown to reduce development of dyskinesia when used as the first-line agent [Rascol et al. 2006; Ferreira and Rascol, 2000; Olanow etal. 2000], but patients will eventually require levodopa treatment to control symptoms. Several reports indicate that the time of onset of motor complications does not change, whether levodopa was started first or added later to the dopamine agonist [Constantinescu etal. 2007; Rascol etal. 2000].
In addition to the oral route, other modes of administration of levodopa have also been investigated by several researchers. Intravenously administered levodopa is effective although relatively impractical for the chronic treatment of patients with Parkinson's disease [Juncos etal. 1987]. Levodopa is not sufficiently soluble to be administered via the transdermal route [Pfeiffer, 2002]. A continuous delivery system via the intraperitoneal or intraduodenal routes might be a better alternative [Bredberg etal. 1994]. 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 [Bredberg et al. 1994; Deleu etal. 1991]. Infusion of carbidopa/levodopa or levodopa through a duodenal tube can facilitate increased mobility and functional ability in individuals with Parkinson's disease when conventional drug therapy is unsuccessful in achieving desired outcomes [Fowler and Bergen, 1993; Kurlan et al. 1988].
The clinical use of dopamine agonists now incorporates a variety of delivery techniques. For example, apomorphine, which relies on parenteral administration for maximum bioavailability [Poewe and Wenning, 2000; Pietz et al. 1998], may be delivered via rectal, intranasal, sublingual and subcutaneous routes. In routine clinical practice, apomorphine is administered via the subcutaneous route only. Meanwhile, rotigotine and lisuride have both been formulated for delivery via skin patches (Johnston etal. 2005). A prolonged-release oral ropinirole preparation is another method tried with success towards continuous dopaminergic stimulation [Jost etal. 2008; Stocchi et al. 2008; Tompson and Vearer, 2007; Pahwa etal. 2007b].
Parkinson's disease is characterized by a progressive degeneration of dopaminergic neurons and the subsequent reduction of striatal dopamine levels [Obeso etal. 2000b]. 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 (Agid, 1991). This is due to the compensatory mechanisms which include an increase in dopaminergic activity in the substantia nigra, downregulation of dopamine transporters, and upregulation of postsynaptic dopamine receptors in the striatum [Obeso etal. 2004; Obeso etal. 2000b; Albin etal. 1995]. Under normal physiological conditions dopamine neurons have relatively constant rates of tonic activity [Grace and Bunney, 1984a; Grace and Bunney, 1984b]. However, increased firing in association with rewards and an unexpected stimulus [Suri, 2002] does occur. Reuptake into presynaptic terminals ensures that extracellular concentrations of dopamine remain constant. 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 in downstream neurons and consequent alterations in neuronal firing patterns that are thought to underlie the development of motor complications [Chase and Oh, 2000; Obeso etal. 2000b; Obeso etal. 2000a].
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 [Hardoff etal. 2001]. In the early stages of oral levodopa treatment, patients with Parkinson's disease experience extensive benefit from the drug, however, with chronic treatment, the duration of benefit after each dose becomes progressively shorter. Patients begin to experience fluctuations in motor response alternating between on response with a good antiparkinson effect and off response when levodopa does not adequately control motor symptoms. Fluctuations may also occur in nonmotor symptoms such as psychological, autonomic and sensory symptom [Obeso et al. 1994; Chase et al. 1989; Marsden and Parkes, 1977]. This occurs because the degenerating dopaminergic terminals are no longer able to adequately buffer the exogenous levodopa [Chase and Oh, 2000]. Whilst degeneration continues, synaptic dopamine levels fluctuate with dosing of oral levodopa leading to supraphysiological levels after dosing, followed by a dopamine-depleted state towards drug clearance [Nutt, 2001]. Dopamine receptors are thus stimulated in an abnormal intermittent fashion, inducing molecular changes within the striatum and other parts of the brain [Calon etal. 2003a, 2003b]. This is due to pharmacodynamic changes in the action of levodopa [Chan etal. 2005a, 2005b].
Parkinson's disease patients typically develop dyskinesias several years after starting levodopa therapy. Dyskinesias typically occur in association with high plasma concentrations of levodopa - known as ‘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. This is known as diphasic dyskinesia. Some patients can also develop ‘off'-period dystonia accompanied by pain and sustained posturing known as ‘off-period dyskinesia'.
Dyskinesias develop within months of starting levodopa therapy in a subgroup of young-onset Parkinson's disease, advanced Parkinson's disease patients, and patients with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced parkinsonism, who have more severe loss of nigral neurons [Schrag and Quinn, 2000; Ballard et al. 1985].
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 [Olanow et al. 2006; Nutt et al. 2000]. In patients with advanced Parkinson's disease, continuous infusion of levodopa or a dopamine agonist has been shown to provide long-lasting and dramatic improvement of established motor complications [Nutt etal. 2000; Stocchi etal. 2002]. 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 [Block etal. 1997].
Experience with continuous infusions of levodopa and dopamine agonists has shown several potential advantages over the conventional intermittent dopaminergic stimulation with oral drugs [Obeso etal. 1994; Chase etal. 1989]. Given this evidence, 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 [Olanow etal. 2006]. This can be achieved through a continuous enteral infusion of a water-soluble form of levodopa. This technique reduces both off periods and dyskinesias in clinical studies [Antonini et al. 2007; Nilsson etal. 2001; Nyholm and Aquilonius, 2004; Kurth etal. 1993]. 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.
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. Levodopa is an acidic drug and needs to be given in a large volume of fluid; thus, dermal administration is not practical [Stocchi etal. 1992]. 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. Titration of levodopa dosage is easy with this method. Another advantage is that other Parkinson's medications such as oral levodopa and dopamine agonists can be eliminated when this method is used.
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.
Kurth and colleagues examined ten patients with Parkinson's disease suffering severe motor fluctuations. This double-blind, placebo-controlled, crossover trial of duodenal infusion of levodopa/carbidopa was conducted to determine if this technique improved the duration of functional ‘on’ time by reducing plasma levodopa level variability. With infusion, seven patients experienced increased functional ‘on’ hours and a decreased number of ‘off’ episodes. However, two patients were slightly worse and one patient experienced no benefit. All ten patients had significantly decreased variability in levodopa levels permitting better titration of levodopa dosage to individual requirements. Five patients continued to use infusion 12-20 months after completion of the study. The authors concluded that patients with Parkinson's disease who experience severe motor fluctuations may benefit from duodenal infusion with an improved and prolonged response to medication [Kurth etal. 1993].
Nyholm and colleagues compared daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in 24 patients with advanced Parkinson's disease. Motor fluctuations and quality of life (QoL) were the outcome measures. Patients with motor fluctuations and dyskinesias were studied in a randomized crossover design to compare individualized conventional treatment for three weeks with intraduodenal infusion of a levodopa/carbidopa gel for another 3 weeks. Functional on time was assessed by blinded assessors and patient self-assessment of motor performance and QoL assessment was also completed.
Infusion therapy improved the functional ‘on’ interval from 81% to 100% (p<0.01). This improvement was accompanied by a decrease in ‘off’ state (p<0.01) and no increase in dyskinesias. Median Unified Parkinson's Disease Rating Scale (UDPRS) scores decreased from 53 to 35 in favor of infusion (p<0.05). QoL was improved, and adverse events were similar for both treatment strategies [Nyholm etal. 2005].
Syed and coworkers reported long-term experience using enteral levodopa infusions in 22 patients with Parkinson's disease with severe motor fluctuations [Syed etal. 1998]. Amelioration of intractable dyskinesias was the most important factor that determined whether patients chose to continue using the infusion pump system. Mechanical and physical problems associated with enteral access were the most common reasons for which patients discontinued pump use. Nearly all patients continued to have dramatically increased on time for the duration of follow up. They suggested that technically less cumbersome systems that provide continuous dopaminergic stimulation are worth developing [Syed et al. 1998].
Between 1991 and 1998, Nilsson and coworkers used continuous daytime administration of levodopa through a transabominal port in 28 advanced Parkinson's disease patients over a total period of 1045 months [Nilsson etal. 2001]. A stable suspension of levodopa and carbidopa (DuodopaTM) was developed. Patients were characterized by early onset, long history of disease, treated with levodopa therapy. The reason for infusion was in all cases related to on-off fluctuations. All patients experienced a general improvement after the introduction of continuous treatment. There were no severe complications reported. A follow-up study showed continued positive effect after 4-7 years of continuous duodenal infusion [Nilsson etal. 2001].
A comparative review of subcutaneous apomorphine, subthalamic nucleus deep brain stimulation (STN-DBS), and continuous duodenal levodopa reported that apomorphine infusion reduced the daily off time but did not improve dyskinesias, and long-term treatment was associated with impulse control disorders. STN-DBS provided motor benefit, but was associated with behavioral changes including attempted suicide. Duodenal levodopa produced significant clinical benefit without behavioral changes and allowed patients to discontinue all other Parkinson's disease medications. The author concluded that duodenal levodopa should be considered in Parkinson's disease patients with advanced disease [Antonini, 2007]. The same author reported significant improvement in UPDRS score and QOL after duodenal dopa infusion [Antonini etal. 2008, 2007].
Stocchi and colleagues compared continuous infusion (levodopa methyl ester 125 mg/hr) along with oral carbidopa with intermittent doses of a standard oral formulation of levodopa in the same patients over a 6 months period. Continuous infusion was reported to provide significant improvements in both ‘off’ periods and dyskinesias [Stocchi etal. 2005]. Two other recently reported studies also highlighted the beneficial effect of enteral infusion despite the technical difficulties associated with the administration [Eggert etal. 2008; Nyholm etal. 2008]. Though the list of the reviewed studies is limited, all of them have documented the advantage of continuous duodenal infusion of dopa over conventional oral therapy.
Oral dopaminergic agonists with long half-lives and continuous transdermal or subcutaneous delivery of dopamine agonists are used to provide near continuous dopaminergic stimulation.
Apomorphine, a nonergot derivative, is a potent, directly acting dopamine receptor agonist. Apomorphine has high affinity to D4 receptors, lower affinity to D2, D3, D5, and a lowest affinity to D1-like dopamine, serotonin and adrenoreceptors. Motor fluctuations are common and distressing for patients with advanced Parkinson's disease. Subcutaneous apomorphine injections can be a valuable adjunctive therapy [Haq etal. 2007].
Subcutaneous apomorphine provides rapid, effective relief of off episodes associated with advanced Parkinson's disease [Pahwa etal. 2007a]. It is effective for rapid rescue from hypomobility, with a magnitude of motor improvement similar to that of levodopa [Obering etal. 2006]. The effect begins within 20 minutes after dosing and lasts approximately 100 minutes. Therapeutic rescue doses are 2-6 mg, and patients typically require approximately three rescue doses per day [Obering etal. 2006]. Dyskinesia improvement is correlated with a reduction in oral medication and with the final apomorphine dose (p<0.05) [Katzenschlager etal. 2005]. A prospective study confirmed a marked dyskinesia reduction with continuous subcutaneous apomorphine therapy [Katzenschlager etal. 2005]. This supports the concept that replacement of short-acting oral antiparkinsonian medications with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesia in Parkinson's disease [Katzenschlager et al. 2005] . However, apomorphine is associated with a clinically significant potential to cause nausea and orthostatic hypotension, and to cause psychiatric complications [Obering et al. 2006] . Apomorphine warrants wider application in treating advanced Parkinson disease but the high cost of the drug, the necessity of concomitant treatment for prevention of side-effects, the subcutaneous administration, and side-effects associated with the drug, restrict its use [Rudzinska and Szczudlik, 2007].
A comparative study between STN-DBS and apomorphine showed that STN-DBS resulted in greater reduction in dopaminergic medications and provided 24-hour motor benefit. However, STN-DBS, unlike apomorphine, appears to be associated with significant worsening on neuropsychological testing resulting in long-term behavioral problems in some patients [De Gaspari etal. 2006]. In summary, continuous apomorphine can reduce the off time by more than 50% of cases and it markedly reduces pre-existing levodopa-induced dyskinesias [Poewe and Wenning, 2000; Colzi etal. 1998]. In comparison with other dopamine agonists, apomorphine is less likely to induce dopamine dysregulation syndrome [Poewe and Wenning, 2000].
Rotigotine is a lipid-soluble, nonergot, D3, D2, D1 dopamine receptor agonist that has demonstrated efficacy as an alternative therapeutic option in both early and advanced Parkinson's disease. It is uniquely formulated as a transdermal patch delivery system allowing for continuous, once-daily administration and better patient compliance. The transdermal 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 [Giladi etal. 2007]. A double-blind placebo controlled trial showed rotigotine consistently demonstrated statistically significant and clinically relevant efficacy over placebo in patients with early Parkinson's disease, as assessed by significantly greater improvement with time in the UPDRS scores [Jankovic etal. 2007]. The most common side effects with rotigotine included a high incidence of local reactions, nausea and somnolence. The rotigotine transdermal system was well tolerated at doses up to 6 mg/24 h [Jankovic etal. 2007]. It is also useful in patients who have difficulties with oral medications because of dysphagia.
The transdermal route avoids fluctuating gastrointestinal absorption due to delayed gastric emptying and avoids hepatic first-pass effects [Baldwin and Keating, 2007]. If side-effects occur, the patch can easily be removed, leading to accelerated termination of such effects. Furthermore, rotigotine is metabolized renally and hepatically, and the hepatic metabolism occurs via a multitude of cytochrome enzymes thus lessening the risk of drug-drug interactions [Watts etal. 2007].
Overnight switch to rotigotine was convenient, well tolerated, and effective for control of Parkinson's disease signs and symptoms for subjects previously receiving low-to-moderate doses of oral dopaminergic agonists [Lewitt etal. 2007a]. Transdermal rotigotine also significantly improved ‘off’ time in subjects with Parkinson disease not optimally controlled with levodopa [Lewitt etal. 2007b]. As in the previous study, the main adverse effects were generally mild or moderate and include application site reactions, somnolence and nausea [Pham and Nogid, 2008]. However, the rotigotine patch has been temporarily withdrawn from the US and European market because of problems related to crystallization of the drug in the patches, which causes unreliable drug delivery.
Lisuride, a potent soluble dopamine agonist and was the first drug to be used for chronic subcutaneous treatment in Parkinson's disease [Stocchi etal. 1988]. A prospective comparison of oral levodopa versus lisuride infusion showed that patients receiving lisuride infusions experienced a significant reduction in both motor fluctuations and dyskinesias compared with patients receiving standard dopaminergic therapies [Stocchi etal. 2002]. Another study, comparing intravenous infusion of levodopa versus intravenous lisuride, showed that levodopa was superior to lisuride in controlling fluctuations [Ruggieri etal. 1988]. A significant number of patients treated with lisuride reported psychiatric side effects thus reducing its therapeutic usefulness [Ruggieri etal. 1989; Vaamonde etal. 1991]. Unusual coronary vasospasm is reported with intravenous use of this drug [Capria et al. 1987] but some other authors have questioned cardiac side-effects of lisuride [Hofmann etal. 2006]. Lisuride is considered relatively safe and is under investigation as a patch for treatment of parkinsonism.
A ropinirole 24-hour release preparation has been newly introduced onto the market and is effective in treating early Parkinson's disease [Stocchi etal. 2008]. Switching from the previous ropinirole immediate-release formulation to the prolonged-release formulation can be done overnight and the acceptance and tolerability are good. The advantages of this preparation are once-daily dosing, faster titration and more stable plasma levels [Jost etal. 2008]. 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 [Tompson and Vearer, 2007]. This drug was found to be a good adjunct therapy in patients with Parkinson's disease not optimally controlled with levodopa and can improve both motor and nonmotor Parkinson's disease symptoms, while permitting a reduction in adjunctive levodopa dose [Pahwa etal. 2007b].
Several treatment options are available to evoke continuous dopaminergic stimulation. Duodenal infusion of levodopa appears to be the most promising when compared with other methods such as subcutaneous apomorphine, transdermal rotigotine and subcutaneous lisuride. Large randomized controlled trials will be required before this therapy becomes widely accepted.
O.K. Sujith, Pacific Parkinson's Research Center, WesBrook Mall, UBC, Canada and Chief Neurologist and Movement Disorder specialist, Kannur Medical college. Email: ac.cbu.egnahcretni@htijus.
Carol Lane, University Of British Columbia, Canada.