Pain in Parkinson's Disease With Motor Fluctuations.

Study Overview
=================
Brief Summary
-----------------
Pain (spontaneous pain) is a fundamental non-motor symptom (NMS) of Parkinson's disease (PD) that is prevalent throughout the condition and often unrecognized and undertreated. The study of the scalp laser-evoked potentials (LEPs) (evoked pain) allows a non-invasive exploration of pain central pathways in humans. This technique proved useful in elucidating the physiopathology underlying different pain syndromes. This study has been conceived to study spontaneous pain (and/or evoked pain by laser stimulation) in PD patients (with or without pain) with motor fluctuations under drugs-on (Safinamide Metansolfonato or Rasagilina Mesilato).

Detailed Description
-----------------
Pain (spontaneous pain) is a fundamental non-motor symptom (NMS) of Parkinson's disease (PD) that is prevalent throughout the condition and often unrecognized and undertreated. Different types of pain have been described in association with PD including musculoskeletal, dystonic, central and neuropathic pain. Although musculoskeletal pain is the most commonly reported, a number of patients experience multiple types of pain which are more frequent and disabling in the intermediate phase of disease and which ultimately have a significant negative impact on the patient's quality of life. Despite its relevance, the pathophysiological mechanisms underlying pain in PD are yet to be fully understood. An abnormal nociceptive input processing in the central nervous system leading to hypersensitivity to evoked pain probably underlies all the different pain types experienced by PD patients and also intervene in pain-free PD patients. Additional factors including female gender, depression, disease duration, motor complications, postural abnormalities, medical conditions associated with painful symptoms (osteoporosis, rheumatic or degenerative joint disease,) probably contribute to the quality and distribution of spontaneous pain. Abnormalities in pain processing may be the consequence of decreased basal ganglia dopaminergic neurotransmission, as dopamine has been demonstrated to modulate pain perception in supraspinal regions involved in the pain pathways, including insula, anterior cingulate cortex, thalamus and periaqueductal grey. Furthermore, a neurodegeneration involving non-dopaminergic systems (such as g-aminobutyric acid, glutamate, noradrenaline, and serotonin) that modulate pain processing in other regions of the central nervous systems may also play a relevant role. The variegated pain dimension experienced by PD patients makes its therapeutic management a demanding challenge for clinicians. The study of the scalp laser-evoked potentials (LEPs) (evoked pain) allows a non-invasive exploration of pain central pathways in humans. This technique proved useful in elucidating the physiopathology underlying different pain syndromes. Some data show that LEPs are altered in PD, in both pain-free PD patients and in PD patients with different kinds of pain, with amplitude reduction in N2/P2 component. Acute levodopa challenge had no effect in normalizing the decreased pain threshold/LEPs observed in PD patients in early Parkinson's disease while in PD patients with motor complications it partially increased pain threshold. This is consistent with the hypothesis that motor complications and pain may share common pathophysiological mechanisms which include not only dopaminergic but also non-dopaminergic systems dysfunction (25).This study has been conceived to study spontaneous pain (and/or evoked pain by laser stimulation) in PD patients (with or without pain) with motor fluctuations under drugs-on (Safinamide Metansolfonato or Rasagilina Mesilato).

Official Title
-----------------
Spontaneous and Evoked Pain in Parkinson's Disease With Motor Fluctuations: an Observational, Prospective, Clinical and Neurophysiological Study in Patients Under L-dopa Add on Therapies.

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: safinamide metansolfonato (12 weeks)
* Drug: safinamide metansolfonato (12 weeks)
* Drug: rasagilina mesilato (12 weeks)
* Drug: rasagilina mesilato (12 weeks)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PD patients with or without pain willing to participate in this study and able to sign the written informed consent To be included in the PD with pain group, the patient's intensity of pain must be moderate to severe over the last month, as reported by a numerical rating scores (NRS≥4) despite the optimal dopaminergic treatment No modification of dopaminergic drugs and analgesic therapy with FANS during the 28 days before starting the enrollment in this study. Diagnosis of idiopathic PD of ≥3 years duration Hoehn and Yahr stage I-III during OFF time Motor fluctuations (>1.5 hours' OFF time/day) Patients who would have been treated with add-on therapy irrespective to the present protocol Exclusion Criteria: Patients under (or with previous assumptions) monoamine oxidase inhibitor therapy. Late-stage PD experiencing severe, disabling peak-dose or biphasic dyskinesia, or unpredictable or widely swinging symptom fluctuations de novo patients, patients in early stage or non-fluctuating patients Evidence of dementia (MMSE <24) Sign and symptoms suggestive of atypical parkinsonism Major psychiatric illnesses Severe and progressive medical illnesses Concomitant diseases potentially causing acute or chronic pain (i.e., rheumatologic conditions, severe polyneuropathy, and spine injuries) Treatments with tri-tetracyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), opioids, neuroleptics, barbiturates and phenothiazines, pregabalin and gabapentin Any type of retinopathy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PD with PAIN<br>12 patients will undergo add-on drugs therapy with safinamide metansolfonato. | Drug: safinamide metansolfonato (12 weeks)<br>* safinamide metansolfonato<br>|
| PD without PAIN<br>12 patients will undergo add-on drugs therapy with safinamide metansolfonato. | Drug: safinamide metansolfonato (12 weeks)<br>* safinamide metansolfonato<br>|
| PD with PAIN rasagilina<br>12 patients will undergo add-on drugs therapy with rasagilina mesilato. | Drug: rasagilina mesilato (12 weeks)<br>* rasagilina mesilato<br>|
| PD without PAIN rasagilina<br>12 patients will undergo add-on drugs therapy with rasagilina mesilato. | Drug: rasagilina mesilato (12 weeks)<br>* rasagilina mesilato<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Latency (ms) of N1/P1 complex. | Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group. | Change from baseline at 12 weeks | 
| Latency (ms) of N2/P2 complex. | Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group. | Change from baseline at 12 weeks | 
| Amplitude (microvolt) of N1/P1 complex. | Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group. | Change from baseline at 12 weeks | 
| Amplitude (microvolt) of N2/P2 complex. | Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group. | Change from baseline at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body localization | The presence of pain (yes/no, dichotomous variable) in one or more body parts: head, upper limbs, lower limbs, shoulders, neck, trunk , lumbar back, pelvis, knees. | Change from baseline at 12 weeks | 
| King's Pain Scale for Parkinson's Disease | (score) | Change from baseline at 12 weeks | 
| Italian version of the brief pain inventory short form | (score) | Change from baseline at 12 weeks | 
| Clinical global impression of change | (score) | Change from baseline at 12 weeks | 
| The 39-Item Parkinson's Disease Questionnaire (PDQ-39) | (score) | Change from baseline at 12 weeks | 
| Numeric Rating Scale (NRS) | (score) | Change from baseline at 12 weeks | 
| Unified Parkinson's Disease Rating Scale | (score) | Change from baseline at 12 weeks | 
| Total daily off time | Total daily off time will assessed by patient diaries reporting frequency and duration of the off periods (hours) | Change from baseline at 12 weeks | 
| Off time following the first morning L-dopa dose | (hours) | Change from baseline at 12 weeks | 
| Age | Age | One timepoint | 
| Gender | (male/female) | One timepoint | 
| Schooling | (years) | One timepoint | 
| Job | type of job | One timepoint | 
| Weight | (kg) | One timepoint | 
| Disease duration | (years) | One timepoint | 
| Age at PD onset | (years) | One timepoint | 
| Laterality of PD symptom onset | (right, left, bilateral) | One timepoint | 
| Most Affected Side | (right, left, bilateral) | One timepoint | 
| Pain symptoms at PD onset | (yes, no) | One timepoint | 
| Dominant phenotype | (Tremor, Bradikinetic/rigid, Mixed) | One timepoint | 
| Modified H&Y | (score) | One timepoint | 
| Pharmacologic therapy for PD | Pharmacologic therapy | One timepoint | 
| Comorbilities | Comorbilities | One timepoint | 
| Mini-Mental State Examination | (score) | One timepoint | 
| Montreal Cognitive Assessment (MoCA) | (score) | One timepoint | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Safinamide, Pain, Parkinson