Etude physiopathologique de la douleur dans la maladie de Parkinson : approches pharmacologique, en neuroimagerie et évaluation des effets de la stimulation cérébrale profonde du noyau sous-thalamique

Les douleurs sont un symptôme très fréquent dans la maladie de Parkinson et peuvent être de différents types. Dans ce travail, nous nous sommes intéressés aux douleurs neuropathiques centrales qui pourraient résulter d'une modification centrale du traitement de l'information douloureuse. En effet, des anomalies de perception douloureuse existent chez les patients parkinsoniens avec une hypersensibilité à la douleur et une hyperactivité des aires cérébrales de la nociception. Une des hypothèses avancées est que ces anomalies pourraient être liées au déficit dopaminergique caractéristique de la maladie de Parkinson. Nous avons testé cette hypothèse de l'implication du système dopaminergique dans les douleurs neuropathiques centrales en évaluant l'effet d'un agoniste dopaminergique sur la perception douloureuse d'une part et en testant la corrélation entre le déficit dopaminergique et la douleur d'autre part. Les résultats de ce premier volet montrent que ce système dopaminergique n'est vraisemblablement pas impliqué dans les anomalies de perception douloureuse et la survenue de douleurs neuropathiques centrales chez les patients. L'hypothèse alternative, à tester dans de futures études, est celle de l'implication d'autres systèmes monoaminergiques comme le système noradrénergique. Le second volet de cette thèse a permis de montrer que la stimulation cérébrale profonde du noyau sous-thalamique avait un effet sur l'intensité de la douleur, sur le seuil nociceptif et l'activité cérébrale liée à la douleur chez des patients souffrant de douleurs neuropathiques centrales. Elle pourrait donc se révéler être un traitement efficace pour ces douleurs de la maladie de Parkinson.One of the most disabling and frequent symptom of Parkinson's disease (PD) is pain. PD patients can suffer from different types of painful symptoms. In this work, we were interested in central neuropathic pain. Pathophysiological basis of this type of pain remains to clarify. A central modification of pain processing has been suggested in PD with a hypersensitivity to pain and abnormal activations of areas involved in pain processing in patients with PD. One hypothesis is that these abnormalities in pain perception could be related to central dopamine deficiency, one of the neuropathological hallmarks of Parkinson's disease. Indeed, basal ganglia have been shown to be involved in pain processing. This work evaluated the role of dopaminergic system in pain perception in two different ways: one evaluating the effect of a dopamine agonist on pain perception and the other testing the correlation between dopamine deficiency and clinical parameters of pain. Results showed that dopaminergic system is probably not involved in pain perception abnormalities and in the occurrence of central neuropathic pain in Parkinson's disease. Others monoaminergic systems, such as the noradrenergic system, could thus be involved and it would be interesting to test this hypothesis in future studies. The other part of our work showed that subthalamic deep brain stimulation had a significant effect on pain threshold, pain-induced activity in positron emission tomography and pain intensity in patients suffering from central neuropathic pain. Deep brain stimulation of this target could thus be an interesting treatment of pain in Parkinson's disease

Emerging analgesic drugs for Parkinson's disease

Introduction: Pain affects between 40 and 85% of Parkinson's disease (PD) patients. It is a frequently disabling and overlooked feature, which can significantly reduce health-related quality of life. Unfortunately, there are no universally recommended treatments for this condition. Areas covered: Evidence about the efficacy and safety of available analgesic treatments is summarized in this review. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of pain in PD. Protocols for efficacy and safety assessment of novel analgesic therapies are discussed. Finally, critical aspects of study protocol design such as patient selection or outcomes to be evaluated are discussed. Expert opinion: Preliminary results indicate that duloxetine, cranial electrotherapy stimulation, rotigotine, subthalamic or pallidum nuclei stimulation or lesion or levodopa could be effective for treating pain in PD. Similarly, some case reports indicate that repetitive transcranial magnetic stimulation (rTMS) or apomorphine could be effective for relieving painful off-period dystonia. Clinical trials with rTMS or oxycodone/naloxone prolonged-release tablets for neuropathic pain or botulinum toxin for off-period dystonia are underway. Success of clinical trials about analgesic strategies in PD will depend on the selection of the right PD population to be treated, according to the type of pain, and the proper selection of study outcomes and follow-up of international recommendations.Fil: Perez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Francia. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Rey, María Verónica. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Francia. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Dellapina, Estelle. Université Toulouse III Paul Sabatier; FranciaFil: Pellaprat, Jean. Université Toulouse III Paul Sabatier; FranciaFil: Brefel Courbon, Christine. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; FranciaFil: Rascol, Olivier. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Franci

Étude physiopathologique de la douleur dans la maladie de Parkinson (approches pharmacologique, en neuroimagerie et évaluation des effets de la stimulation cérébrale profonde du noyau sous-thalamique)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Naftazone in advanced Parkinson's disease: An acute L-DOPA challenge randomized controlled trial

International audienceIntroduction: There is an unmet need to better control motor complications in Parkinson's disease (PD). Naftazone, which exhibits glutamate release inhibition properties, has shown antiparkinsonian and antidyskinetic activity in preclinical models of PD and in a clinical proof of concept study.Methods: We conducted a double-blind randomized placebo-controlled cross-over trial in PD patients with motor fluctuations and dyskinesia testing naftazone 160 mg/day versus placebo for 14 days. The two co-primary endpoints were the area under curve (AUC) of motor (MDS-UPDRS part III) and dyskinesia (AIMS) scores during an acute levodopa challenge performed at the end of each period. Secondary endpoints were UDysRS and axial symptoms scores during the challenge; AIMS, UDysRS, and time spent with or without dyskinesia the day before the challenge. The primary analysis was performed in the per protocol population.Results: Sixteen patients were included in the analysis. There was no difference between naftazone and placebo for the AUC of MDS-UPDRS III (-89, 95%CI[-1071; 893], p = 0.85), and AIMS (70, 95%CI[-192; 332], p = 0.57). At the end of treatment periods, AIMS score tended to be lower with naftazone than placebo (4.4 ± 3.4 versus 6.7 ± 4.4, p = 0.07), but UDysRS scores and other secondary outcomes were not different. Naftazone was safe and well tolerated.Conclusions: This study did not confirm previous results on the efficacy of naftazone on dyskinesia nor motor fluctuations highlighting the problem of translating results obtained in preclinical models into clinical trials. Further investigation of naftazone may be conducted in PD with longer treatment duration

Descriptive analysis of the French NS-Park registry: Towards a nation-wide Parkinson's disease cohort?

International audienceIntroduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's. The French clinical research network for PD (NS-Park) has created a national patient registry to i)report medical activity of Parkinson Expert Centers (PECs) to the Ministry of Health, ii)facilitate PD patients pre-screening for clinical trials, iii) provide a source for pharmaco-epidemiology studies.Objective: Assess the French Parkinsonian population at a nation-wide level and discover new clinical characteristics.Methods: In this feasibility study, PECs prospectively collected clinical data in a standardized manner. The population main clinical characteristics are described, focusing on motor and non-motor symptoms and treatments, assessing its representativeness. By using an unbiased clustering with multiple correspondence analysis (MCA), we also investigate potential relationships between multiple variables like symptoms and treatments, as clues for future studies.Results: Between 2012 and 2016, among 11,157 included parkinsonian syndromes, 9454 (85%) had PD. MCA identified various profiles depending on disease duration. Occurrences of motor complications, axial signs, cognitive disorders and Levodopa use increase over time. Neurovegetative symptoms, psychiatric disorders, sleep disturbances and impulse control disorders (ICDs) seem stable over time. As expected, ICDs were associated to dopaminergic agonist use but other associations, such as ICDs and sleep disturbances for instance, or anxiety and depression, were found.Conclusions: Our results report one of the biggest PD registries ever reported and demonstrate the feasibility of implementing a nation-wide registry of PD patients in France, a potent tool for future longitudinal studies and clinical trials' population selection, and for pharmaco-epidemiology and cost-effectiveness studies

Trial of Lixisenatide in Early Parkinson’s Disease

International audienceBackground: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease.Methods: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent.Results: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%.Conclusions: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease