Pulsatile Dopaminergic Stimulation Research Articles

Continuous Dopaminergic Stimulation Improves Cortical Maladaptive Changes in Advanced Parkinson's Disease.

With the progression of Parkinson's disease (PD), pulsatile treatment with oral levodopa causes maladaptive changes within basal ganglia-thalamo-cortical circuits, which are clinically expressed as motor fluctuations and dyskinesias. At the level of the motor cortex, these changes may be detected using transcranial magnetic stimulation (TMS), as abnormal corticospinal and intracortical excitability and absent response to plasticity protocols. We investigated the effect of continuous dopaminergic stimulation on cortical maladaptive changes related to oral levodopa treatment. Twenty patients with advanced PD were tested using TMS within 1 week before and again 6 months after the introduction of levodopa-carbidopa intestinal gel. We measured resting and active motor thresholds, input/output curve, short interval intracortical inhibition curve, cortical silent period, and response to intermittent theta burst stimulation. Patients were clinically assessed with Part III and Part IV of the Movement Disorders Society Unified Parkinson's Disease Rating Scale. Six months after the introduction of levodopa-carbidopa intestinal gel, motor fluctuations scores (P = 0.001) and dyskinesias scores (P < 0.001) were reduced. Resting and active motor threshold (P=0.012 and P = 0.015) and x-intercept of input/output curve (P=0.005) were also decreased, while short-interval intracortical inhibition and response to intermittent theta bust stimulation were improved (P=0.026 and P=0.031, respectively). Changes in these parameters correlated with clinical improvement. In patients with advanced PD, switching from intermittent to continuous levodopa delivery increased corticospinal excitability and improved deficient intracortical inhibition and abnormal motor cortex plasticity, along with amelioration of motor fluctuations and dyskinesias. Continuous dopaminergic stimulation ameliorates maladaptive changes inflicted by chronic pulsatile dopaminergic stimulation. © 2022 International Parkinson and Movement Disorder Society.

High levodopa plasma concentration after oral administration predicts levodopa-induced dyskinesia in Parkinson's disease

IntroductionIn patients with Parkinson's disease (PD), pulsatile dopaminergic stimulation may be a primary cause of levodopa-induced dyskinesia (LID). We aimed to investigate the correlation between levodopa pharmacokinetics (PK) and LID in PD. MethodsWe retrospectively reviewed the consecutive series of 255 PD patients without LID who underwent PK assessments with 100 mg levodopa. The type of peripheral decarboxylase inhibitor used in the PK assessments was determined by the usual prescription of the formulations of levodopa (10 mg carbidopa [n = 185] and 25 mg benserazide [n = 70]). ResultsDuring a median follow-up of 32 months (IQR, 16–49 months), 73 patients (29%) developed LID. Compared with patients who did not develop LID (PD–LID−), those who developed LID (PD–LID+) were younger (p = 0.003) and had significantly higher maximum levodopa concentration (Cmax) (p = 0.002) and area under the curve (p < 0.001), LEDD (p < 0.001), and improvement of motor symptoms (p = 0.009). In the multivariate Cox proportional hazards models, Cmax and AUC were associated with incident LID (Hazard Ratio [HR] 1.11, 95% confidence interval [CI] 1.03–1.19 and HR 1.13, 95% CI 1.03–1.24, respectively). In addition, younger age, benserazide use, LEDD, and MAOBI use were associated with incident LID. ConclusionHigh levodopa plasma concentration after oral administration was associated with incident LID in patients with PD.

Levodopa treatment and dendritic spine pathology.

ABSTRACTParkinson'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 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

DopAmide: Novel, Water-Soluble, Slow-Release l-dihydroxyphenylalanine (l-DOPA) Precursor Moderates l-DOPA Conversion to Dopamine and Generates a Sustained Level of Dopamine at Dopaminergic Neurons.

Long-term l-dihydroxyphenylalanine (l-DOPA) treatment of Parkinson's disease (PD) is associated with motor complications known as l-DOPA-induced dyskinesias (LID) and on/off fluctuations, which are linked to unsteady pulsatile dopaminergic stimulation. The objective of this study was to improve l-DOPA treatment by slowing and stabilizing dopamine (DA) production in the brain and increasing water solubility to provide a rescue therapy for PD. We synthesized l-DOPA-amide, a novel l-DOPA precursor called DopAmide. DopAmide is water soluble and, as a prodrug, requires hydrolysis prior to decarboxylation by the aromatic l-amino acid decarboxylase (EC 4.1.1.28; AAAD). In the 6-OH-dopamine (6-OHDA)-lesioned rats, DopAmide maintained steady rotations for up to 4 h compared with 2 h by l-DOPA, suggesting that this rate-limiting step generated a sustained level of DA at dopaminergic neurons. Pharmacokinetic studies showed elimination half-life of l-DOPA in the plasma after DopAmide treatment of t1/2 = 4.1 h, significantly longer than t1/2 = 2.9 h after treatment with l-DOPA, consistent with the 6-OHDA results. The slow conversion of DopAmide to l-DOPA provides a sustained level of DA in the dopaminergic cells, shown by the long 6-OHDA steady rotations. The water solubility and improved bioavailability may help reduce medication frequency associated with l-DOPA treatment of PD. Sustained levels of DA might lower the super-sensitization of DA signaling and potentially attenuate l-DOPA adverse effects.

Levodopa‐carbidopa intestinal gel in advanced Parkinson's disease: Final 12‐month, open‐label results

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces l-dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Continuous infusion of levodopa-carbidopa intestinal gel in Parkinson's disease.

Evaluation of: Olanow CW, Kieburtz K, Odin P et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 13(2), 141-149 (2014). Levodopa-induced motor complications, including motor fluctuations and dyskinesia, can be a major source of disability for Parkinson's disease patients. The development of levodopa-induced motor complications has been attributed to the pulsatile dopaminergic stimulation characteristic of conventional oral levodopa regimens. This is a review of a 12-week, randomized, controlled, double-blind, double-dummy study of continuous jejunal infusion of levodopa-carbidopa intestinal gel to determine if the continuous infusion of levodopa reduces motor complications in Parkinson's disease. Results demonstrated that levodopa-carbidopa intestinal gel significantly reduced off-time without increasing troublesome dyskinesia compared with standard oral levodopa therapy. Adverse effects were common in both the levodopa-carbidopa intestinal gel and placebo groups and were related primarily to the infusion hardware.

Role of magnetic resonance spectroscopy in differentiating parkinsonian syndromes of various etiologies

Role of magnetic resonance spectroscopy in differentiating parkinsonian syndromes of various etiologies

A long-term, open-label study of levodopa–/INS;carbidopa intestinal gel in advanced Parkinson's disease patients: Functional and health-related quality-of-life endpoints

Background: Some Parkinson's disease (PD) motor complications are associated with pulsatile dopaminergic stimulation. Levodopa–/INS;carbidopa intestinal gel (LCIG) provides continuous drug infusion via an intrajejunal percutaneous gastrostomy tube.

A long-term, open-label study of levodopa–/INS;carbidopa intestinal gel in advanced Parkinson's disease patients: safety and motor-symptom endpoints

Background: Motor complications in Parkinson's disease (PD) are associated with pulsatile dopaminergic stimulation. Levodopa–/INS;carbidopa intestinal gel (LCIG) provides continuous drug infusion via an intrajejunal percutaneous gastrostomy tube.

Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson’s Disease Patients

Motor complications of Parkinson's disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa-carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total levodopa and carbidopa doses were 1,580 (403) and 395 (101) mg, respectively. Mean (SD) C(avg) (μg/mL) were 2.9 (0.84) for levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (C(max)-C(min))/C(avg)] in levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2-16 of infusion. Accordingly, the within-subject coefficients of variation in levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.

Treatment of Parkinson Disease, Time and Dosage

Current available treatment for Parkinson disease has many drawbacks: single action on the nigrostriatal pathway, no halt of disease progression, pulsatile dopaminergic stimulation, complex treatment regimens, and motor complications. Compliance with treatment may be irregular in a variable number of patients. Factors such as age, education, complexity of posology, stage of disease, disease comprehension, cognitive function, or family support significantly influence compliance either in a positive or negative way. The consequences of noncompliance include withdrawal symptoms, increase in number of admissions, or, in severe cases, hyperthermia syndrome secondary to levodopa deficit in the case of infradose. In situations of overdose, dyskinesia or psychiatric complications may arise. The ideal treatment should have the potency of levodopa but not its side effects, act on striatal D2 receptors in a continuous way with a single dose and have low potential of addiction. Thus far, simple regimens are only applicable in early stages.

Biodegradable Microspheres Loaded with an Anti-Parkinson Prodrug: An in Vivo Pharmacokinetic Study

During chronic treatment with L-dopa (LD), Parkinsonian patients often experience uncontrolled motor complications due to fluctuations of the plasmatic levels of LD that result in pulsatile dopaminergic stimulation. To overcome these plasmatic fluctuations, a novel prodrug of LD, L-dopa-α-lipoic acid (LD-LA), has been proposed as a tool for achieving continuous dopaminergic stimulation. Due to slower susceptibility toward enzymatic conversion by LD-degrading enzymes (such as catechol-O-methyltransferase and monoamine oxidase), the plasma half-life of this prodrug is longer than that of LD. Moreover, the higher lipophilicity of LD-LA over LD promotes its delivery to the CNS, where the resulting levels of dopamine (DA) are kept high for a longer time than after equimolar administration of LD. To further reduce fluctuations in plasma levels of LD, LD-LA has been entrapped into biodegradable polymeric microspheres to be used as a depot system with the aim to prevent prodrug degradation and to obtain a sustained release of the intact compound. In the present work, a formulation of LD-LA loaded microspheres (characterized for drug loading, size, morphology, thermal properties, and in vitro prodrug release) has been administered subcutaneously to rats, and the resulting levels of LD and DA in plasma and striatal tissue, respectively, have been monitored. A good correlation between the in vitro release kinetics and the time range during which the formulation alters the LD/DA tissue levels in vivo was observed, suggesting that the polymeric microsphere matrix protects the loaded prodrug from chemical and enzymatic degradation and controls its release. Interestingly, LD-LA microspheres provided sustained levels of DA neurotransmitter in the striatum nucleus for up to 4 days after a single administration. In conclusion, a polymeric microsphere formulation of LD-LA is an attractive medicine for treating Parkinson's disease (PD) symptoms, avoiding motor complications.

Levodopa in Parkinson's disease: from the past to the future

Importance of the field: Levodopa is the mainstay of symptomatic treatment for Parkinson's disease (PD). Although other treatments have been developed in the last 30 years, most patients use levodopa in view of its superior efficacy in controlling PD symptoms. Unfortunately, levodopa is associated with long-term motor complications (motor fluctuations and dyskinesias). The main causes of these undesirable effects are the narrowing of the therapeutic window with the natural progression of the disease, pulsatile dopaminergic stimulation due to the short half-life of the drug and erratic absorption. Several studies suggest that PD control could be enhanced by changing the mode of levodopa delivery so as to ensure continuous and stable supply of the drug to the brain. The objective of this text is to review the ascertained strengths and limitations of levodopa in PD, starting from its history, and propose novel modes of usage designed to cover currently unmet medical needs.Areas covered in this review: Medline literature search (from 1973 to date).What the reader will gain: A perspective on the evolution of PD pharmacological treatment.Take home message: Levodopa still is the best treatment for PD. Truly stable and controlled formulations that ensure clinical response should be developed to reduce the undesirable effects that restrict its efficacy.

Rotigotine transdermal delivery for the treatment of Parkinson's disease

Background: Rotigotine is a non-ergot dopamine agonist that has been developed as a new transdermal formulation, and is indicated for use in early (USA and Europe) and advanced (Europe only) Parkinson's disease (PD). The potential advantages of the rotigotine patch include immediacy of effect onset as intestinal absorption in unneeded, constant drug delivery, and ease of use via application of a once-daily adhesive patch. An interesting element of this profile is constant drug delivery, which may avoid pulsatile dopaminergic stimulation, which has been postulated to be related to the development of motor complications. Objective: To consider the evidence surrounding the profile of rotigotine and, in particular, whether its constant delivery system offers significant benefits to the treatment of early and advanced PD. Methods: Source material was identified using a PubMed search for the term ‘rotigotine’ (up to March 2008). The review focuses only on publications related to the rotigotine indication for PD. Results/conclusion: The rotigotine transdermal patch demonstrates clinical efficacy, alongside a tolerability profile that appears to be well within the range of that observed with other non-ergot dopamine agonists. The once-daily patch formulation may favour compliance but, in similarity with the other theoretical advantages of constant drug delivery (for example reduced emergence of motor complications, improved tolerance to peripheral AEs), requires further detailed study.

Rotigotine for the Treatment of Advanced Parkinson's Disease

Background: Rotigotine, a non-ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch is approved by the regulatory authorities for use in all stages of Parkinson’s disease (PD) in Europe and for early-stage PD in the US. For patients with advanced-stage PD and motor fluctuations, approved doses range from 4mg/24 hours to 16mg/24 hours. The rotigotine patch offers a certain number of potential advantages, including faster onset as intestinal absorption is not needed, continuous drug delivery and ease of use via application of a once-daily adhesive patch. An interesting element of this profile is continuous drug delivery, which may avoid the pulsatile dopaminergic stimulation that has been postulated to be related to the development of motor complications.Objective: The aim of this article is to review the pharmacokinetics, pharmacodynamics and clinical efficacy and tolerability of the rotigotine transdermal patch.Methods: Source material was identified using a PubMed search for the term ‘rotigotine’ in articles published up to October 2009 and a review of published congress abstracts. The review focused primarily on publications related to the rotigotine indication for advanced PD.Results and conclusions: The rotigotine transdermal patch demonstrates clinical efficacy and a tolerability profile that appears to be well within the range of that observed with other non-ergot dopamine agonists, except for local skin reactions, which are common with the rotigotine patch. The once-daily patch formulation may encourage compliance; however, as is the case for other theoretical advantages of continuous drug delivery, such as reduced emergence of motor complications and improved tolerance of peripheral adverse events, this requires further detailed study.

Do dyskinesia and pain share common pathophysiological mechanisms in Parkinson's disease?

Plastic changes within the striatum resulting from pulsatile dopaminergic stimulation are thought to lead to dyskinesia in patients with Parkinson's disease (PD). The basal ganglia play a role in processing pain. We hypothesized that the plastic changes that lead to dyskinesia may also mediate pain responses. Our objective was to compare the change in pain sensitivity after levodopa administration between stable responders, fluctuators without dyskinesia, and dyskinetic patients, and to compare pain sensitivity between PD and healthy subjects. Fifty patients with PD were assessed with cold water immersion after overnight withdrawal of dopaminergic medications and again after a standard levodopa challenge, and carefully classified into stable responder (n = 12), fluctuator (n = 15), and dyskinetic (n = 23) groups. Twenty age-matched controls were also tested. PD patients "off"-medication had a lower threshold (P = 0.016) and tolerance (P < 0.0001) to cold pain compared to controls. After levodopa administration, dyskinetic patients experienced a large increase in cold pain threshold (48%) and tolerance (66%) that was absent in stable responders (P = 0.038 and P = 0.015); there was no significant difference in pain sensitivity change scores between the fluctuator and either the stable responder or dyskinetic groups. Our results suggest that dyskinesia and pain may share common pathophysiological mechanisms in PD.

Introduction: The Impact of Continuous Levodopa Infusion in the Treatment of Parkinson's Disease

Parkinson's disease was first described in 1817 by James Parkinson. Based on his observation of only six individuals, Parkinson accurately described the resting tremor and festinate gait, bradykinesia, and postural instability associated with the disease today. Parkinson's disease primarily affects people &gt;50 years of age and causes progressive neurological degeneration, physical disability, and worsening quality of life.Consequently, most currently available drugs aim to restore striatal dopamine signaling. This can be best reached by increasing the supply of dopamine with oral levodopa (L-dopa), but also by stimulating dopamine receptors directly using dopamine agonists, or by inhibiting the reuptake of endogenous dopamine. Unfortunately, mainly due to the short half-life of L-dopa and the erratic absorption of oral L-dopa (causing pulsatile dopaminergic stimulation) these treatment strategies become increasingly ineffective in the course of this disease, and motor complications may further reduce the quality of life in these patients.

Preventing and controlling dyskinesia in Parkinson's disease-A view of current knowledge and future opportunities

Dyskinesia affects ∼30 to 40% of patients with Parkinson's disease but treatment options for the prevention of dyskinesia induction and for the suppression of established dyskinesia are limited. This situation is made more difficult by a poor understanding of the pathphysiology of the processes underlying both the priming for dyskinesia and the manifestations of involuntary movements. Loss of tonic stimulation of striatal dopamine receptors in PD and its replacement by pulsatile dopaminergic stimulation using short acting drugs has been proposed as leading to the abnormalities that cause dyskinesia induction. As a consequence, the concept of continuous dopaminergic stimulation (CDS) was introduced to explain why longer acting dopamine agonists do not produce the same intensity of dyskinesia. Key to these ideas has been the use of both 6-OHDA lesioned rodent models of PD and, in particular MPTP-treated primates. Comparison of the ability to induce dyskinesia of the same dopamine agonists given by pulsatile or continuous administration or more constant administration of Levodopa (L-dopa) has shown that constant drug delivery (CDD) dramatically reduces dyskinesia induction. Similar conclusions have been reached from clinical investigations in PD. Recent studies in MPTP-treated primates have also suggested that switching from pulsatile drug delivery to CDD can be utilized to inhibit dyskinesia expression. However, CDS does explain some important features of dyskinesia induction in PD but it may not apply to early PD when remaining dopaminergic neurones buffer against pulsatile stimulation. In addition, CDS may not apply when comparing between drug classes and it appears that it is CDD which is more important in regulating therapeutic efficacy. Recently, studies in MPTP-treated primates have suggested that a range of nondopaminerigic drugs might be useful in suppressing dyskinesia. These have included 5-HT-1A agonists and α-2 adrenergic antagonists and a variety of other molecular entities. Unfortunately, these findings are not always reproducible in the same models and do not translate into clinically useful effects. Preclinical studies have suggested a number of directions that might be utilized to prevent dyskinesia in PD. However, much of what is proposed is empirically-based and we still do not have a good understanding of why dyskinesia appears, why it persists or how to bring the movements under control. Certainly, the use of CDD can reduce dyskinesia intensity but other factors also influence its appearance and it is these that we need to study at the preclinical level if effective therapies are to be developed. © 2008 Movement Disorder Society

Spotlight on Rotigotine in Parkinson’s Disease†

A transdermal patch formulation of the non-ergolinic dopamine receptor agonist rotigotine (Neupro) is indicated for use as monotherapy in the treatment of early-stage Parkinson's disease or, in the EU, as an adjunct to levodopa across all disease stages. Transdermal rotigotine is an effective and generally well tolerated addition to the armamentarium for the control of Parkinson's disease, with the once-daily transdermal patch system offering several practical advantages and the possible benefits of avoiding pulsatile dopaminergic stimulation. Transdermal rotigotine was superior to placebo in patients with early-stage and advanced Parkinson's disease, although noninferiority to the oral dopamine receptor agonists ropinirole or pramipexole was not consistently demonstrated. Additional active comparator trials would be of interest. In the meantime, transdermal rotigotine offers a convenient new treatment option for patients with Parkinson's disease.

Continuous dopaminergic stimulation: Is it the answer to the motor complications of Levodopa?

Continuous dopaminergic stimulation (CDS) is a treatment strategy hypothesized to avoid or reduce the motor complications of long-term levodopa therapy, motor fluctuations, and dyskinesia, by preventing or reversing sensitization induced by pulsatile dopaminergic stimulation. The CDS hypothesis is itself based on several hypotheses. First, tonic dopaminergic stimulation is physiological. Second, sensitization is undesirable and should be reversed. Third, reduction of off time and dyskinesia can be induced simultaneously. Finally, clinical studies substantiate the CDS hypothesis. The evidence for these hypotheses is reviewed, and the need for randomized clinical trials that rigorously test the CDS hypothesis is emphasized.