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

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.

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