Three Way Interaction Between Gabapentin, Duloxetine, and Donepezil in Patients With Diabetic Neuropathy

Study Overview
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Brief Summary
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The purpose of the study is to determine whether the combination of the the three drugs gabapentin, duloxetine, and donepezil are effective in treating pain in people with diabetic neuropathy or patients with failed low back syndrome (chronic back pain).

Detailed Description
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Neuropathic pain is a complex and likely heterogeneous disorder, and we recognize that clinically useful agents such as opioids, gabapentin, and antidepressants may be effective precisely because they have multiple mechanisms of action at multiple sites. This study, however, will not only provide important mechanistic information regarding one cascade which can be manipulated for analgesia, but will also provide much needed systematic and practical guidance for multi-drug therapy in patients with neuropathic pain. This study in patients with diabetic neuropathic pain and patients with failed low back syndrome, culminate in a quantitative description of interactions between activators of descending noradrenergic activity, norepinephrine transporter inhibitors, and cholinesterase inhibitors to exploit the plasticity of analgesia in chronic pain states. We will focus on practical applications, using clinically approved drugs, including gabapentin (Neurontin®) to activate noradrenergic activity, duloxetine (Cymbalta®) to inhibit the norepinephrine transporter, and donepezil (Aricept®), approved for the treatment of Alzheimer's dementia, but not previously tested to treat neuropathic pain, to inhibit cholinesterase. After the baseline measurements and physical examination patients will be trained to use a Personal Digital Assistant (PDA) to answer questions about their diabetic neuropathic pain or their chronic back pain. Upon successful completion of these tasks the patients will be randomized to receive one of the drug choices or placebo (inactive pill). The study will last for a total of 16 weeks and includes 5 visits to the research center with each visit lasting approximately 2 hours.

Official Title
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Three Way Interaction Between Gabapentin, Duloxetine, and Donepezil in Patients With Diabetic Neuropathy

Conditions
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Diabetic Neuropathic Pain, Chronic Low Back Pain

Intervention / Treatment
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* Drug: donepezil
* Drug: duloxetine
* Drug: donepezil 2.5 mg and duloxetine 30mg
* Drug: placebo
* Drug: gabapentin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of diabetic neuropathy Age 18-80 Willing to temporarily discontinue gabapentin or monoamine reuptake inhibitors upon entry into the study Exclusion Criteria: Pregnancy Allergy to study medications Uncontrolled narrow-angle glaucoma Currently being treatment with thioridazine (Mellaril) Unstable medical conditions including cardiac, pulmonary, renal or hepatic diseases Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days of randomization

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Donepezil<br>Donepezil 5 mg once per day for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8. | Drug: donepezil<br>* Group 1: Will receive donepezil 5mg once a day<br>* Other names: Aricept®;Drug: gabapentin<br>* Week 8: all subjects will have open label gabapentin added to their randomized study medication<br>* Other names: neurontin;|
| Active Comparator: Duloxetine<br>Group 2: Will receive duloxetine 30 mg twice a day for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8. | Drug: duloxetine<br>* Group 2: Will receive duloxetine 30 mg twice a day<br>* Other names: Cymbalta®;Drug: gabapentin<br>* Week 8: all subjects will have open label gabapentin added to their randomized study medication<br>* Other names: neurontin;|
| Active Comparator: Donepezil + Duloxetine<br>Group 3: Will receive a combination of donepezil 2.5 mg and duloxetine 30mg for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8. | Drug: donepezil 2.5 mg and duloxetine 30mg<br>* Group 3: Will receive a combination of donepezil 2.5 mg and duloxetine 30mg<br>* Other names: Aricept®;Drug: gabapentin<br>* Week 8: all subjects will have open label gabapentin added to their randomized study medication<br>* Other names: neurontin;|
| Placebo Comparator: Placebo<br>Group 4:Will receive placebo pills. Gabapentin will be titrated in all groups beginning at week 8. | Drug: placebo<br>* Group 4: Will receive placebo pills<br>Drug: gabapentin<br>* Week 8: all subjects will have open label gabapentin added to their randomized study medication<br>* Other names: neurontin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scale for Pain | The primary outcome measure is the visual analog scale (VAS) for pain, a 10 cm line upon which the subject marks their intensity of pain. The line is anchored on the left as No pain at all and on the right as The worst pain imaginable. The score is the number of millimeters from the left origin of the line. The primary outcome measure for each period was the average value of all assessments for that period (2 weeks of measures for baseline, 6 weeks of measures for test drug alone, 6 weeks of measures for test drug plus gabapentin, and 2 weeks of measures for gabapentin alone). | Study completion (16 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asymmetric Diabetic Proximal Motor Neuropathy, Diabetic Autonomic Neuropathy, Diabetic Neuralgia, Diabetic Neuropathy, Painful, Neuralgia, Diabetic, Low back pain, chronic