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

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).

Study Overview

• Status: Terminated
• Conditions: Chronic Low Back Pain; Diabetic Neuropathic Pain
• Intervention / Treatment: Drug: donepezil; Drug: gabapentin; Drug: duloxetine; Drug: donepezil 2.5 mg and duloxetine 30mg; Drug: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Wake Forest University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: February 8, 2008
• First Submitted That Met QC Criteria: February 8, 2008
• First Posted (Estimate): February 21, 2008

Study Record Updates

• Last Update Posted (Actual): September 11, 2018
• Last Update Submitted That Met QC Criteria: August 13, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Diabetic Neuropathy, Painful; Diabetic Autonomic Neuropathy; Diabetic Neuralgia; Asymmetric Diabetic Proximal Motor Neuropathy; Neuralgia, Diabetic; Low back pain, chronic
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Back Pain; Low Back Pain; Neuralgia; Diabetic Neuropathies; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Anti-Anxiety Agents; Anticonvulsants; Serotonin and Noradrenaline Reuptake Inhibitors; Antimanic Agents; Nootropic Agents; Cholinesterase Inhibitors; Duloxetine Hydrochloride; Gabapentin; Donepezil
• Other Study ID Numbers: IRB00003943; 5R01NS057594 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Raw IPD will not be shared

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No