Donepezil Compared to Placebo in Patients With Chronic Neuropathic Pain

Investigators are currently examining in the laboratory the mechanisms which lead to
sprouting of noradrenergic fibers in the spinal cord in models of chronic pain as well as the
mechanisms that lead to a novel noradrenergic - cholinergic circuit in the spinal cord. In
addition to examining the circumstances which generate this increased capacity for analgesia
and the mechanisms by which they occur, investigators will test in this protocol whether
approved and experimental treatments for neuropathic pain exploit this increased capacity.

This study is in patients with neuropathic pain taking gabapentin or pregabalin, and will
test the clinical relevance of these preclinical data by comparing placebo to the
cholinesterase inhibitor. Investigators focus not only on mechanistic hypotheses in the
laboratory studies, but also on practical applications, using clinically approved drugs,
including gabapentin and pregabalin to activate noradrenergic activity and donepezil
(Aricept®), approved for the treatment of Alzheimer's dementia, but not previously tested to
treat neuropathic pain, to inhibit cholinesterase. Each of these drugs may act by mechanisms
in addition to those involved in descending noradrenergic inhibition, but investigators
hypothesize that the therapeutic strength of their combination relies heavily on this cascade
engendered by noradrenergic sprouting and altered α2-adrenoceptor function. The proposed
studies will provide critical tests of this hypothesis and critical information to guide more
effective clinical therapy of neuropathic pain.

Inclusion Criteria:

- Diagnosis of diabetic neuropathy or failed back syndrome with neuropathic symptoms

- Age 18-80

- Taking a stable dose of gabapentin or pregabalin

Exclusion Criteria:

- Pregnant women or women of child-bearing potential not willing to practice a reliable
form of birth control

- Allergy to donepezil or other piperidine derivatives (including fentanyl, alfentanil,
sulfentanil, remifentanyl, demerol, tramadol, loperamide, diphenoxylate, betaprodine,
alphaprodine, ethopropazine, anileridine, piminodine,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),loratadine, fexofenadine

- Unstable medical conditions including cardiac, pulmonary, renal or hepatic diseases
that, in the opinion of the investigator, would preclude patients from finishing the
trial

- Any person with pending litigation

- A history of major psychosis requiring hospitalization within the last three years

- Non-English speaking, illiterate, unable to comprehend consent

- Lack of contact information

- Uncontrolled narrow-angle glaucoma

- Currently being treatment with thioridazine (Mellaril)

- Patients taking opioids will be excluded if they are taking a dosage that exceeds an
equivalent of 30 mg of morphine per day

- Patients taking more than one regular (not rescue) medication for pain

- Patients taking donepezil for dementia

- Patients with a baseline pain score less than 2 (0-10 scale) or greater than 8 (0-10)
will be excluded