Effects of PR Oxycodone and of Levodopa, vs Placebo, on Central Neuropathic Pain in Parkinson's Disease

Study Overview
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Brief Summary
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This study will be conducted in three parallel groups receiving oxycodone, levodopa or placebo, administered as an add-on therapy, in addition to the usual antiparkinsonian treatment. As this study focuses on chronic central neuropathic pain caused by PD, the effects of study treatments will be evaluated after a 10-week treatment period

Detailed Description
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The treatment period (11 weeks) will be divided into three periods: A titration phase of two weeks, during which of the doses of the treatments will be gradually increased in three steps: Level 1 (from D1 to D5): Oxycodone: 10 mg PR/day bid (5 mg PR/5 mg PR) Levodopa: 100 mg/day bid (50 mg/50 mg) Level 2 (from D6 to D10): Oxycodone: 20 mg PR/day tid (10 mg/0 mg/10 mg) Levodopa: 150 mg/day tid (50 mg/50 mg/50 mg) Level 3 (from D11to D15): Oxycodone: 40 mg PR/day tid (20 mg/0 mg/20 mg) Levodopa: 200 mg/day tid (100 mg/50 mg/50 mg) A fixed dose period: the level 3 dose will be maintained for 8 weeks (from D16 to D71). The study treatment will be administered as an add-on therapy, with the usual antiparkinsonian treatment. If patients have side effects at the level 3 dose, a return to the level 2 dose will be authorized. A withdrawal period: The dose of the study treatment will gradually be reduced, over an eight-day period: For patients treated with the level 3 dose for 8 weeks: decrease to the level 2 dose over the first 3 days (from D72 to D74) ; then a decrease to the level 1 dose over the next 3 days (from D75 to D77). The treatment will be stopped completely on D78. The last visit will take place on D79, 2 days after the end of treatment. For patients treated with the level 2 dose: decrease to the level 1 dose over the first 3 days (from D72 to D74), with stopping of the treatment on D75. The last visit will take place on D79, 5 days after the end of treatment.

Official Title
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Evaluation of the Analgesic Effects of Prolonged-release Oxycodone and of Levodopa, Versus Placebo, on Central Neuropathic Pain in Parkinson's Disease: OXYDOPA Trial

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: PR Oxycodone
* Drug: Levodopa
* Drug: Oxycodone Placebo
* Drug: Levodopa placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Parkinson's disease according to the UKPDSBB (United Kingdom Parkinson's Disease Society Brain Bank) criteria Patients suffering from chronic pain (lasting for more than 3 months) Patients suffering from central neuropathic pain caused by PD, Patients with a PD-related central neuropathic pain intensity of at least 3 points on the VAS (average intensity over the last month), Patients with both types of pain (neuropathic and nociceptive) will be included if the neuropathic pain predominates Patients treated with a stable regimen of dopaminergic drugs (levodopa and/or dopamine agonists) for at least 4 weeks before the study dan throughout the study Patients with a stable step 1 analgesic (NSAIDS, acetaminophen) or coanalgesic (antidepressants, antiepileptic) treatment for at least 4 weeks before the study and throughout the study Exclusion Criteria: Patients suffering from another parkinsonian syndrome De Novo patients (patients never before treated with dopaminergic drugs) Patients with intercurrent acute pain Patients suffering from a chronic disease causing pain (rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathy, cancer etc.) Patients treated with neuroleptics Patients with clinically detectable behavioural disorders and addiction Patients with disabling dyskinesias Patients with painful restless legs syndrome Patients with cognitive impairment (MMS < 25) or unable to complete the various scales used in the study Hypersensitivity to oxycodone, levodopa, benserazide or a combination of these drugs Patients treated with opioid drugs (step 2 and 3) Patients treated with non-selective monoamine oxidase inhibitors (MAOI) Patients with severe hepatocellular insufficiency Patients with uncontrolled cardiovascular and pulmonary diseases Persistent constipation that has already resulted in a subocclusive state Patients treated with antiemetic neuroleptics Patients with angle-closure glaucoma Exclusion criteria relating to MRI: Patients with claustrophobia Patients with a hearing aid, cardiac prosthesis, pacemaker, surgical clip Patients refusing to be informed of abnormalities are detected on MRI

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PR oxycodone<br>A titration phase of two weeks, in three steps: Level 1 (from D1 to D5): Oxycodone : 10 mg PR/day bid (5 mg PR/5 mg PR) Levodopa placebo 100 mg/day bid (50 mg/50 mg) Level 2 (from D6 to D10): Oxycodone : 20 mg PR/day tid (10 mg/0 mg/10 mg) Levodopa placebo: 150 mg/day tid (50 mg/50 mg/50 mg) Level 3 (from D11to D15): Oxycodone: 40 mg PR/day tid (20 mg/0 mg/20 mg) Levodopa placebo: 200 mg/day tid (100 mg/50 mg/50 mg) A fixed dose period: the level 3 dose will be maintained for 8 weeks (from D16 to D71). A withdrawal period: | Drug: PR Oxycodone<br>* PR Oxycodone<br>* Other names: PR Oxycontin;Drug: Levodopa placebo<br> <br> |
| Active Comparator: levodopa<br>A titration phase of two weeks, in three steps: Level 1 (from D1 to D5): Oxycodone placebo : 10 mg PR/day bid (5 mg PR/5 mg PR) Levodopa 100 mg/day bid (50 mg/50 mg) Level 2 (from D6 to D10): Oxycodone placebo: 20 mg PR/day tid (10 mg/0 mg/10 mg) Levodopa : 150 mg/day tid (50 mg/50 mg/50 mg) Level 3 (from D11to D15): Oxycodone placebo: 40 mg PR/day tid (20 mg/0 mg/20 mg) Levodopa : 200 mg/day tid (100 mg/50 mg/50 mg) A fixed dose period: the level 3 dose will be maintained for 8 weeks (from D16 to D71). A withdrawal period: | Drug: Levodopa<br>* Levodopa<br>* Other names: Modopar;Drug: Oxycodone Placebo<br>* Placebo of PR Oxycodone<br>|
| Placebo Comparator: Placebo<br>A titration phase of two weeks, in three steps: Level 1 (from D1 to D5): Oxycodone placebo : 10 mg PR/day bid (5 mg PR/5 mg PR) Levodopa placebo 100 mg/day bid (50 mg/50 mg) Level 2 (from D6 to D10): Oxycodone placebo: 20 mg PR/day tid (10 mg/0 mg/10 mg) Levodopa placebo: 150 mg/day tid (50 mg/50 mg/50 mg) Level 3 (from D11to D15): Oxycodone placebo: 40 mg PR/day tid (20 mg/0 mg/20 mg) Levodopa placebo: 200 mg/day tid (100 mg/50 mg/50 mg) A fixed dose period: the level 3 dose will be maintained for 8 weeks (from D16 to D71). A withdrawal period: | Drug: Oxycodone Placebo<br>* Placebo of PR Oxycodone<br>Drug: Levodopa placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average pain intensity | Change in average pain rated on visual analog scale (VAS) intensity between baseline and after 8 weeks | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal pain intensity | Change of maximal pain intensity over the preceding week rated on the VAS | 8 weeks | 
| Functional impact of pain of the Brief Pain Inventory (BPI) | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Neuropathic Pain Symptoms Inventory (NPSI) | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| McGill pain questionnaire (SFMPQ) | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Depression and anxiety: the Hospital Depression and Anxiety (HAD) scale | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Apathy: the Lille Apathy Rating Scale (LARS) | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Fatigue : the Parkinson fatigue scale | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Sleep : the Pittsburgh sleep quality index | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Motor assessment and motor fluctuations: MDS UPDRS (MDS Movement Disorder Society - UPDRS Unified Parkinson Disease Rating Scale) | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Quality of life: Parkinson's Disease Questionnaire 39 items (PDQ-39) | Change in scores between Day 0 and Day 71(Day 71= 8 weeks of treatment) | 8 weeks | 
| Acetaminophen consumption reported in diary | number of pills or capsules reported in patients diary | 8 weeks | 
| Adverse events | Adverse events, evaluated with an open-ended questionnaire | Day 5, Day 10, Day 15, Day 43, Day 71, Day 79 | 
| changes in Resting-state brain network (3T fMRI) | changes in resting-state cerebral networks between Day 0 and Day 71, as assessed by 3T fMRI. | Day 0 /Day 71(Day 71= 8 weeks of treatment) |