Clinical trial NCT00619983
Conditions: Diabetic Neuropathic Pain Chronic Low Back Pain
Keywords: Asymmetric Diabetic Proximal Motor Neuropathy Diabetic Autonomic Neuropathy Diabetic Neuralgia Diabetic Neuropathy, Painful Neuralgia, Diabetic Low back pain, chronic
Sponsor: Wake Forest University
Start date: 2008-02-01; Completion date: 2013-05-01
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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.

Arms: arm 1: Donepezil 5 mg once per day for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8. arm 2: Group 2: Will receive duloxetine 30 mg twice a day for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8. arm 3: 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. arm 4: Group 4:Will receive placebo pills. Gabapentin will be titrated in all groups beginning at week 8.
Interventions: intervention 1: donepezil intervention 2: duloxetine intervention 3: donepezil 2.5 mg and duloxetine 30mg intervention 4: placebo intervention 5: gabapentin
Intervention descriptions: intervention 1: Group 1: Will receive donepezil 5mg once a day intervention 2: Group 2: Will receive duloxetine 30 mg twice a day intervention 3: Group 3: Will receive a combination of donepezil 2.5 mg and duloxetine 30mg intervention 4: Group 4: Will receive placebo pills intervention 5: Week 8: all subjects will have open label gabapentin added to their randomized study medication

Protocol documents:
Prot_SAP_000.pdf: 
3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
Version 8 
October 19, 2010 
Page 1 of 11 
Three way interaction among gabapentin, duloxetine, and donepezil in patients with 
diabetic neuropathy 
 
 
Investigators: James C. Eisenach, M.D.; James C. Crews, M.D.; Tim Houle, Ph.D.,  
 
 
James B. Caress, M.D., Regina Curry, R.N. 
 
 
 
Hypothesis: Based on laboratory studies and our understanding of their mechanism of  
action, there will be a profound positive interaction between two oral drugs approved for 
the treatment of neuropathic pain (gabapentin and duloxetine) and an oral drug approved 
for treatment of dementia (donepezil) to treat patients with chronic pain. 
 
 
Background:  We have recently demonstrated that peripheral nerve injury in rats, which 
results in hypersensitivity to mechanical stimuli and presumably 
chronic pain, also results in increased capacity for analgesia.  
Specifically, nerve injury induces sprouting of noradrenergic 
fibers in the dorsal horn of the spinal cord, accompanied by 
changes in α2-adrenoceptor function and development of a spinal 
α2-adrenoceptor - cholinergic circuit.  These changes likely 
underlie the increased potency and efficacy of intrathecal 
clonidine observed in animals and humans with chronic 
compared to acute pain, but may have considerably wider 
therapeutic implications.  For example, commonly used, oral 
drugs for the treatment of neuropathic pain, gabapentin and 
antidepressants, may depend in part on this noradrenergic 
plasticity for their efficacy.  A summary of the hypothesized 
sites and mechanisms of action of drugs to be studied in this application is shown in the 
adjacent figure.   
Gabapentin
+
Duloxetine
ACh
NE
Donepezil
+
+
Figure : This study will test whether 
1. Gabapentin produces analgesia 
after nerve injury by a spinal 
noradrenergic mechanism, and its 
effects are enhanced by  2. the 
norepinephrine transporter inhibitor, 
duloxetine, and 3. the 
cholinesterase inhibitor, donepezil 


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Anesthesiology 
 
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We 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, we 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, and will culminate in a 
quantitative description of interactions between activators of descending noradrenergic 
activity, norepinephrine transporter inhibitors, and cholinesterase inhibitors to exploit this 
unique plasticity of analgesia in chronic pain states.  We focus not only on mechanistic 
hypotheses in the laboratory studies, but also 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. Each of these drugs may act by 
mechanisms in addition to those involved in descending noradrenergic inhibition, but we 
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. 
 
 
Protocol 
Inclusion Criteria:   
 
A total of sixty-six patients with diabetic neuropathic pain will be recruited from 
the Department of Neurology at Wake Forest University School of Medicine, 
surrounding Piedmont Triad community and we will also have a second site at the 
Cleveland Clinic Foundation in Cleveland Ohio.  Patients with predominant 
neuropathic pain following back surgery will also be enrolled. Approximately 46 


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subjects will be enrolled at WFUHS and 20 will be enrolled from the Pain Clinic at the 
Cleveland Clinic. Wake Forest University Health Sciences will be the coordinating 
center. Jianguo Cheng, MD, will be the PI for the Cleveland Clinic site. Subjects from 
the Cleveland Clinic will follow the same protocol as the WFUHS subjects. 
 
1. Diagnosis of diabetic neuropathy 
2. Age 18-80 
3. Willing to temporarily discontinue gabapentin or monoamine reuptake inhibitors upon 
entry into the study 
Subjects will be able to continue their other prescribed medications maintaining a stable 
dose.  
4.  Diagnosis of failed back syndrome. 
 
Exclusion Criteria:   
1. Pregnant women or women of child-bearing potential not willing to practice a 
reliable form of birth control as specified in the informed consent 
2. Allergy to  duloxetine, gabapentin, donepezil or other piperidine derivatives 
(including fentanyl, alfentanil, sulfentanil, remifentanyl, demerol, tramadol, 
loperamide, diphenoxylate, betaprodine, alphaprodine, ethoprodine, 
anileridine, diminodine, MPTP, loradine, fexofenadine 
3. Unstable medical conditions including cardiac, pulmonary, renal or hepatic 
diseases that, in the opinion of the investigator, would preclude patients from 
finishing the trial 
4. Any person with pending litigation 
5. A history of major psychosis requiring hospitalization within the last three 
years 
6. Non-English speaking, illiterate, unable to comprehend consent 
7. Lack of contact information 
8. Known hypersensitivity to duloxetine or any of the inactive ingredients 


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9. Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days of 
randomization or potential need to use an MAOI during the study or within 5 
days of discontinuation of study drug 
10. Uncontrolled narrow-angle glaucoma 
11. Currently being treatment with thioridazine (Mellaril) 
12.  Patients taking opioids will be excluded if they are taking a dosage that 
exceeds an equivalent of 30 mg of morphine per day  
13. Patients taking more than one regular (not rescue) medication for pain 
14. Patients taking donepezil for dementia 
15. Patients with a baseline pain score less than 2 (0-10 scale) or greater than 8 (0-
10) will be excluded 
Drug Administration (basis of randomization):   
 
Following a two week baseline period, patients will be seen in The General 
Clinical Research Center (GCRC) at Wake Forest University Baptist Medical Center and 
data from the PDA device downloaded and checked for compliance. Patients will be 
randomized, using a balanced and double blind design, to receive either duloxetine, 30 
mg bid, donepezil, 5 mg qd, both duloxetine 30 mg and donepezil 2.5 mg qd, or placebo 
for the next 12 weeks.  All randomizations will include study medication to be taken 
twice a day to maintain the blinding for all groups. Placebo pills will be provided in 
addition to the study medications for group 1 and group 4 will take two placebo pills.  At 
the end of 6 weeks, patients will return to The General Clinical Research Center and data 
from the PDA downloaded and checked for compliance.  All patients will then receive 
gabapentin, 400 mg three times daily, titrated twice a week by telephone interview with 
the research nurse or investigator for three weeks up to a maximum of 3200 mg per day. 
Titration up or down will be determined by presence and severity of side effects and 
efficacy of analgesic treatment, using a standardized interview.  Subjects will then be 
maintained on this gabapentin dose for 3 more weeks.  At the end of this 6 week period 
of gabapentin administration, patients will return to The General Clinical Research 
Center and data from the PDA downloaded and checked for compliance.  Their 
experimental treatment (placebo, duloxetine, donepezil, or combination) will then be 


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Anesthesiology 
 
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stopped for two weeks, with daily PDA entry and titration of gabapentin twice weekly by 
standardized telephone interview. 
 
Experimental Design:   
The study will be conducted over a period of 16 weeks; consisting of 2 weeks 
baseline (no study drug), weeks 3-8 randomized drug assignment, weeks 9-14 of open 
label gabapentin added to randomized drug assignment (gabapentin to be titrated twice 
weekly up to a maximum dose of 3200mg for three weeks), weeks 15-16 randomized 
drug assignment is discontinued while maintaining gabapentin.  During this time patients 
will make 5 visits to the GCRC (screening visit with a 2, 8, 14 week and 16 week study 
termination visit with a +1/-1 day window).  The first visit will entail a brief patient 
history and a physical exam. In addition, patients will complete primary and secondary 
measurements, including: McGill short form pain questionnaire (primary) and Profile of 
Mood States-Short Form (POMS-SF).  The McGill short form pain questionnaire will be 
administered twice daily via PDA (personal digital assistant) and POMS will be used for 
patients to record total mood disturbance and pain. Study subjects will be trained to use 
their PDA at their initial visit.   
Following the two week baseline period, subjects will be seen in the GCRC and 
data will be downloaded and checked for compliance.  Patients will be randomized, using 
a balanced double blind design, to receive either duloxetine, 30mg bid, donepezil, 5 mg 
qd, both duloxetine 30mg and donepezil 2.5 mg qd, or placebo for the next 12 weeks.  
At the end of week 8, subjects will return to the General Clinical Research Center 
and data from the PDA downloaded and checked for compliance.  All subjects will then 
receive gabapentin, 400 mg three times daily, titrated twice a week by telephone 
interview with the research nurse or investigator for three weeks up to a maximum of 
3200 mg per day.  Titration up or down will be determined by presence and severity of 
side effects and efficacy of analgesic treatment, using a standardized interview.  Subjects 
will then be maintained on the Gabapentin dose for 3 more weeks. 
At the end of week 14, patients will return to the General Clinical Research 
Center and data from the PDA downloaded and checked for compliance.  Their 


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experimental treatment (placebo, duloxetine, donepezil, and combination) will then be 
stopped for two weeks, with daily PDA entry and titration of gabapentin twice weekly by 
standardized telephone interview. 
 
Screening 
 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week
6 
Week
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week 
12 
Week 
13 
Week 
14 
Week 
15 
Week 
16 
 
Visit 
 1 
 
Visit 
2 
 
 
 
 
 
Visit 
3 
 
 
 
 
 
Visit 
4 
 
Visit  
5 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain 
Questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PDA 
Instructions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PDA Download 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded Study 
Med   
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Gabapentin  
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Outcome Measures:   
Pain intensity measurements will be recorded twice daily, in the a.m. and p.m. 
using McGill short form pain questionnaire displayed on the personal digital assistant 
(PDA).  The SF-MPQ is comprised of 15 descriptors (11 sensory; 4 affective) with an 
intensity scale from 0-3 (3 being the most severe), present pain intensity (PPI), and 
Visual Analog Pain Scale (VAS).  The VAS will serve as the study’s primary outcome 
measure.     
 
Statistical Analyses:  
 
All data will be analyzed using the most recent version of SPSS (SPSS Inc., 
Chicago, IL).    Prior to performing analyses related to the aims and hypotheses, 
descriptive statistics will be computed to examine if assumptions needed for parametric 
analysis are met.  Our previous studies of daily pain reports from neuropathic pain 


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patients (1) have indicated that such reports can be expected to be approximately 
normally distributed. If parametric assumptions are not met, standard transformations will 
be used to make the data more normal. An intent-to-treat analysis will be undertaken for 
all participants that receive at least one study dose (with last observation carried forward 
for drop-outs) with no attempts being made to impute missing data. A two-tailed 
probability value of .05 will be used for statistical significance criterion in all analyses. 
 
To examine differences in the primary outcome of twice-daily pain reports as a 
function of “medication group” and “study phase”, a Linear Mixed Model will be used. 
Subjects will be treated as a random variable, with the average of the daily pain reports 
nested within subject. A first-order autoregressive error term will be used to account for 
the repeated measures within subjects. Although all observations will be used to specify 
the model, only the observations from the last week (the optimal therapeutic dose) of 
each study phase (“baseline”, “study med”, and “gabapentin”) will be used to evaluate 
the hypothesis. In essence, this allows changes in the dependent variable of pain reports 
to be modeled by two ANCOVAs (controlling for baseline). Group (placebo, duloxetine, 
donepezil, and duloxetine + donepezil) differences in pain reports will be evaluated 
separately at end of treatment alone and at end of treatment with gabapentin portions of 
the study. A significant group effect will indicate that mean self-reported pain scores 
differed significantly by treatment arm assignment during that phase of the study.  If a 
main effect is found, post hoc analyses will be conducted to indicate the location of the 
differences and to index the degree of change exhibited by study group. 
 
In addition to the primary analyses, we will examine pre-post changes in 
disability measures and psychometric measures, global assessments of change, and 
medication use. Each of these outcomes will be examined using General Linear Models 
(GLM), examining for differences in group either at one time period or as a function of 
study phase, as appropriate. Further, because the study design will result in a time-series 
of pain reports for each subject, we will fully utilize the available data by creating 
individualized interrupted time-series analysis models for each subject. Within each 
phase, increases in dose will be modeled as a gradual, permanent intervention. We will 
utilize ARIMA models (2) to account for the unique data structure that our design results 


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(i.e., diurnal variation in AM and PM reports). These analyses will better elucidate the 
nature of individual differences in the medication responses and identify the dose-
response function for each medication condition. 
 
Statistical Power Considerations:  
 
For the proposed study all power calculations are based on the primary analysis of 
the primary outcome measure (daily pain reports). ANCOVA analyses were chosen to 
evaluate the primary outcome as they have repeatedly been shown to be the most 
powerful technique for these comparisons (3). Our previous diary studies examining 
novel agents on neuropathic pain (1) have demonstrated that high levels of visual analog 
pain reporting are common, M = 60.5, and that substantial variation is often observed, 
even within day-to-day reporting, SD = 14. Nevertheless, first-order autocorrelation 
among observations is often observed, r = .20. For the present study, we are preparing for 
a considerable placebo effect of 20%. Because of the novel nature of the agents being 
studied, we would like to detect differences as small as 5% between the active treatment 
and placebo groups (i.e., a 25% reduction in pain from baseline). Using Cohen’s 
formulation for ANCOVA (6) (f = .25, r =.50 between phases) with adjustment (4) for 
the calculation of our repeated assessment of each study phase (7 observations 
contributed by each subject at each phase, first-order autocorrelation = .20), we estimate 
that an n = 15 for each medication group (15 x 4 = N = 60) will provide power = .80. It is 
of note that the proposed sample size indicates the number of participants that take at 
least one dose of the study drugs (i.e., recruitment will end when N = 60 participants have 
taken at least one dose of study medication). Further, the 16 week trial, with two 
observations per day provides a sufficient number of observations (n ~ 224 
observations/subject) to incorporate the interrupted time-series analysis strategy for the 
secondary analyses (5). 
 
Adverse Events/Side Effects:  


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The most common side effects of duloxetine observed in diabetic peripheral 
neuropathy groups include but are not limited to nausea, excessive drowsiness, dizziness, 
constipation, dry mouth, excessive sweating, decreased appetite and weakness.  
 
The most common side effects of gabapentin are dizziness, excessive drowsiness, 
peripheral edema, nausea, dry mouth, constipation and ataxia.  Other side effects include 
tiredness, flu syndrome, double or blurred vision, shakiness, and abnormal thinking.  
Common side effects of donepezil include (but are not limited to) nausea, 
diarrhea, vomiting, weight loss, if experienced usually subside within a few days.  .  
Adverse events that were also reported during clinical trials conducted with donepezil 
include:  headache, pain in various locations, accident, fatigue, fainting, loss of appetite, 
bruising, muscle cramps, arthritis, insomnia, dizziness, depression, abnormal dreams, 
sleepiness, and frequent urination.   
 
Additional warnings per package insert of donepezil are:   
Anesthesia: ARICEPT®, as a cholinesterase inhibitor, is likely to exaggerate 
succinylcholine-type muscle relaxation during anesthesia. 
Cardiovascular Conditions: Because of their pharmacological action, 
cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular 
nodes. This effect may manifest as bradycardia or heart block in patients both with and 
without known underlying cardiac conduction abnormalities. Syncopal episodes have 
been reported in association with the use of ARICEPT®. 
Gastrointestinal Conditions: Through their primary action, cholinesterase 
inhibitors may be expected to increase gastric acid secretion due to increased cholinergic 
activity. Therefore, patients should be monitored closely for symptoms of active or occult 
gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., 
those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-
inflammatory drugs (NSAIDS). Clinical studies of ARICEPT® have shown no increase, 
relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal 
bleeding. 


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Anesthesiology 
 
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ARICEPT®, as a predictable consequence of its pharmacological properties, has 
been shown to produce diarrhea, nausea and vomiting. These effects, when they occur, 
appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. In most 
cases, these effects have been mild and transient, sometimes lasting one to three weeks, 
and have resolved during continued use of ARICEPT®. 
Genitourinary: Although not observed in clinical trials of ARICEPT®, 
cholinomimetics may cause bladder outflow obstruction. 
Neurological Conditions: Seizures: Cholinomimetics are believed to have some 
potential to cause generalized convulsions. However, seizure activity also may be a 
manifestation of Alzheimer's Disease. 
Pulmonary Conditions: Because of their cholinomimetic actions, cholinesterase 
inhibitors should be prescribed with care to patients with a history of asthma or 
obstructive pulmonary disease. 
     
Risks:  
 
Risks of the medications are described above.  There is an overlap in side effects 
between gabapentin and duloxetine regarding sedation.  As such, one could see enhanced 
sedation with this mixture.  This should be minimized in the current study, since 
gabapentin is being titrated according to side effects.  Additionally, there is a risk of 
temporary exacerbation of chronic pain during the washout period or if drugs are 
ineffective.  Please note that we are studying patients who are failing current analgesic 
therapy, and this study may benefit these patients by providing a novel combination of 
medications otherwise not used.  Data will be stored in a secure location. Additionally, 
the personal digital assistants (PDA) will hold no personal identification information. 
 
Data Safety Monitoring Plan 
Data will be continually monitored by the study coordinator and reported to the principal 
investigator who will review the data and all adverse events after each subject is studied.  
Serious and unexpected adverse events will be reported to the IRB within 24 hours of 
discovery. 


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References: 
1.  
Harden RN, Houle TT, Remble TA, et al. Topiramate for phantom limb pain: a 
 
time-series analysis. Pain Med 2005;6:375-8. 
2.  
Box GEP, Jenkins GM, Reinsel GC. Time-Series Analysis: Forecasting and 
 
Control. 3rd ed. New Jersey: Prentice-Hall, 1994. 
3.  
Senn S. Repeated measures in clinical trials: analysis using mean summary 
 
statistics and its implication for design. Stat Med 1994;13:197-8. 
4.  
Vickers AJ. How many repeated measures in repeated measures designs? 
 
Statistical issues for comparative trials. BMC Med Res Meth 2003;3:1-9. 
5.  
Box GEP, Tiao GC. A change in level of a nonstationary time series. Biometrika 
 
1965;52:181-92. 
6. 
Cohen JC. Statistical Power Analysis for the Behavioral Sciences, second   
 
edition. Lawrence Erlbaum Associates: Hillsdale, NJ. 1988. 
 
 

ICF_001.pdf: 
Version 10 
April 16, 2010 
Page 1 of 9 
 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00003943 
Meeting Date Approved 9/28/2011 
Version Valid Until: 9/27/2012 
Department/Section of Anesthesiology 
 
 
 
 
 
 
 
 
 Three way interaction among gabapentin, duloxetine, and donepezil in 
patients with diabetic neuropathy 
James C. Eisenach, M.D., Principal Investigator 
 
 
INTRODUCTION 
You are being asked to read the following document as a part of the informed consent process.  
The informed consent process is to inform you of the risks and benefits involved in the study so 
you can make a free decision whether or not to participate.  Informed consent includes having 
the study fully explained to you, an opportunity to ask questions, your questions answered to 
your satisfaction and a written informed consent to read and sign.  Your participation is 
voluntary. 
 
Research studies are designed to gain scientific knowledge that may help other people in the 
future. You may or may not receive any benefit from being part of the study. There may also be 
risks associated with being part of research studies.  
 
You are being asked to participate in this research study to be performed by Dr. James C. 
Eisenach in the General Clinical Research Center (GCRC) at Wake Forest University Baptist 
Medical Center. There will be approximately sixty-six subjects involved in this research project.  
The length of participation will last approximately 16 weeks. 
 
You are being asked to take part in this study because you have been diagnosed with diabetic 
neuropathic pain or you have had surgery on your back and you continue to have chronic lower 
back pain. 
 
Diabetic nerve pain can happen when people with diabetes develop damage to the nerves 
throughout their body. This “nerve damage” or “neuropathy” can lead to numbness, pain and 
weakness in the hands, arms, feet, and legs. This same type of nerve pain can also develop after 
you have had back surgery.  
 
 


Version 10 
April 16, 2010 
Page 2 of 9 
 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00003943 
Meeting Date Approved 9/28/2011 
Version Valid Until: 9/27/2012 
WHY IS THIS STUDY BEING DONE? 
The purpose of this research study is to test whether the combination of the following medicines, 
including donepezil (used for treatment of Alzheimer’s disease), gabapentin (used to treat 
neuropathic pain), and duloxetine (used for the treatment of depression and diabetic neuropathic 
pain) will have a greater reduction in pain if taken together than if taken separately. Donepezil, 
gabapentin, and duloxetine are FDA approved drugs. What we learn in this study may lead to 
future research studies to try to find effective combinations of medicine therapy for pain 
management. In this study these drugs will be compared to placebo. In this study these drugs will 
be compared to placebo (placebo contains no active medication). 
 
Placebos are used in research studies to see if the drugs being studied really do have an effect. 
  
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
There will be about 66 people included at all sites across the country included in the study. 
Approximately 46 people will be enrolled at this site; Wake Forest University Baptist Medical 
Center. Subjects will be assigned to one of four groups. All four groups will be treated with 
gabapentin in addition to the assigned study drug for the last eight weeks of the study. 
 
Group 1: Will receive donepezil 5mg.   
Group 2: Will receive duloxetine 30 mg.   
Group 3: Will receive a combination of donepezil 2.5 mg and duloxetine 30mg.  
Group 4: Will receive placebo pills.   
 
This is a double blind study which means that neither you nor your doctor will know which 
group you are assigned to during the study. This information is available in case of an 
emergency.  Regardless of the group you are in, you will be instructed to take one study pill 
twice each day. All four groups will be treated with gabapentin in addition to the assigned study 
drug for the last eight weeks of the study.   
 
 
WHAT IS INVOLVED IN THE STUDY? 
The study lasts 16 weeks. We ask that you do not add any new medications or receive injections 
to treat your pain during this 16 week study period. You will have five visits to the GCRC.  
 
First visit: 
 We will ask you questions about your pain.  You will complete some questionnaires and 
computer tests that describe the type of pain you have as well as how you are feeling. 
 You will receive a physical exam.   
 If you are a woman who is able to become pregnant, you will give a urine sample for a 
pregnancy test.  If you are pregnant, you cannot participate in this study.   
 If you are taking any of the medications we are using in the study (i.e. donepezil, duloxetine, or 
gabapentin) or are taking a certain type of antidepressant (monoamine reuptake inhibitors), you 
will stop taking them.   
 We will give you a Personal Digital Assistant (small, computer-like device that is held in your 
hand, commonly known as a PDA) to take home, and ask that you turn it on twice a day (every 


Version 10 
April 16, 2010 
Page 3 of 9 
 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00003943 
Meeting Date Approved 9/28/2011 
Version Valid Until: 9/27/2012 
morning and evening) to answer the questions.  These questions are about your pain. This visit 
will take about four hours. 
 
Second visit (two weeks later): 
 We will connect your PDA to a computer and check if you have been answering the questions 
twice a day.  We will do this at every visit. 
 If you are still eligible for the study, you will be randomized into one of the four study groups 
described above. Randomization means that you are put into a group by chance. It is like 
flipping a coin. You will have a one in four chance of being placed in any group.  Neither you 
nor the study doctor will know which group you are in but we can find that out in case of 
emergency. 
 You will start the study drug. You will take the blinded study drug as prescribed for the next 
six weeks.  
 You will answer the questions using your PDA every morning and evening. 
 This visit will take about two hours. 
 
Third visit (six weeks later): 
 You will bring your blinded drug and PDA so we can check to make sure you are taking the 
study drug properly and answering all your questions.   
 We will add the drug gabapentin to the study drug you are already taking.  We will start you 
out with 400mg of gabapentin three times a day.   The study doctor or study nurse will call you 
twice a week to ask you a set of standard questions about your pain and any side effects you 
have.  We will adjust your dose of gabapentin based on your answers.  The highest gabapentin 
dose will be 3200 mg per day.  This titration (adjusting of the dose) of the gabapentin will last 
about 3 weeks.  Once we determine your maximum needed dose, you will maintain that dose 
for another 3 weeks.   
 You will still take your other study drug during this time and continue using your PDA to 
answer the questions in the morning and evening.  
 This visit will take about two hours. 
 
Fourth visit (six weeks later): 
 You will bring your blinded drug, gabapentin and PDA so we can check to make sure you are 
taking the study drug and gabapentin properly and answering all your questions.   
 You will stop taking your assigned study drugs (placebo, donepezil, duloxetine, or 
donepezil/duloxetine combination) at this visit but you will keep taking the gabapentin for two 
more weeks. 
 You will continue using your PDA to answer the questions in the morning and evening. 
 This visit will take about two hours. 
 
Fifth visit (two weeks later): 
 You will bring your gabapentin and PDA so we can check to make sure you are taking the 
gabapentin properly and answering all your questions.   
 You will return the PDA and study drugs provided during the study.  At this last visit, you will 
stop all study drugs.  
 This visit will take about two hours. 


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 You will be instructed to resume your prescribed medication schedule.  
 
 
HOW LONG WILL I BE IN THE STUDY? 
You will have five study visits over a 16 week period. Your study participation will be complete 
after the fifth visit to the GCRC. 
 
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences.  
 
WHAT ARE THE RISKS OF THE STUDY? 
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff.  The following risks exist, and side effects may happen.  You should discuss 
these with your doctor.  There also may be other side effects that we cannot predict. 
 
The most common side effects of duloxetine observed in diabetic peripheral neuropathy patients 
include but are not limited to nausea, excessive drowsiness, dizziness, constipation, dry mouth, 
excessive sweating, decreased appetite and weakness. 
 
The most common side effects of gabapentin are dizziness, excessive drowsiness, peripheral 
edema, nausea, dry mouth, constipation and ataxia.  Other side effects include tiredness, flu 
syndrome, double or blurred vision, shakiness, and abnormal thinking.  
 
Common side effects of donepezil include (but are not limited to) nausea, diarrhea, vomiting, 
weight loss. These symptoms usually subside within a few days.  Adverse events that were also 
reported during clinical trials conducted with donepezil include:  headache, pain in various 
locations, accident, fatigue, fainting, loss of appetite, bruising, muscle cramps, arthritis, 
insomnia, dizziness, depression, abnormal dreams, sleepiness, and frequent urination.   
 
With donepezil, there are some known potential risks involving this class of drugs.  If you are 
planning on having surgery, you would need to tell the doctor you are taking this medication.  It 
could increase the effects of your anesthesia depending on the drugs they treat you with.  There 
is a risk of fainting episodes, known as syncope, associated with this drug. If you have a history 
of ulcer disease or you are taking nonsteroidal anti-inflammatory drugs (like aspirin, Advil, 
Motrin, Aleve, and others), we will watch closely for any signs of ulcer disease and intestinal 
bleeding.  Although not observed in clinical trials with donepezil, this class of drugs may cause 
difficulty urinating.  This class of drugs is also believed to have some potential to cause seizures.  
If you have a history of asthma or coronary obstructive pulmonary disease (COPD), you should 
take caution in taking this medication. 
 
As with all medications, side effects may include an allergic reaction.  Allergic reactions may 
range from minor reactions, such as itching or rash, to major, life threatening reactions which can 
result in death. 
 


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Institutional Review Board 
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Version Valid Until: 9/27/2012 
Any drug has possible side effects.  The drugs used in this study may cause some or none of the 
side effects listed.  In addition there is always the risk of uncommon or previously unknown side  
 
effects occurring.  If you have any kind of unusual or unexpected symptoms, you should report 
them immediately to your study doctor. 
 
Also, there is a risk of a temporary increase of chronic pain during the washout period (the first 
two weeks of the study) or if the study drugs do not work well for you.   
 
Taking part in this research study may involve providing information that you may consider 
confidential or private.  This may make you feel uncomfortable or embarrassed. There is always 
a risk this information may be accidentally released. The PDA you will use will contain no 
personal identification information about you. Efforts, such as coding research records and 
keeping them secure so that only study staff have access to them, will be made to keep your 
information safe, but we cannot guarantee absolute confidentiality and privacy.  
 
Reproductive risks:  
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives (the 
pill), intrauterine device (IUD), DepoProvera, Norplant, tubal ligation, or vasectomy of the 
partner (with confirmed negative sperm counts) in a monogamous relationship (same partner). 
An acceptable, although less reliable, method involves the careful use of condoms and 
spermicidal foam or gel and/or a cervical cap or sponge. We encourage you to discuss this issue 
further with your physicians if you have any questions. 
 
Pregnant women are excluded from participation in this study. If you are a sexually active 
woman of childbearing potential and have not been using a reliable method of birth control, two 
negative pregnancy tests performed 15 days apart are required to check for possible early 
pregnancy prior to starting treatment.  During the study, you must use one of the reliable 
methods of birth control described above.   
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
You may benefit from this study by getting better pain relief than with your regular pain 
medications.  We also hope the information learned from this study will benefit other people in 
the future. 
 
WHAT OTHER CHOICES ARE THERE? 
Your participation is voluntary. Your alternative is to continue with your treatment as prescribed 
by your physician and not participate in this study. 
 
WHAT ABOUT THE USE, DISCLOSURE AND CONFIDENTIALITY OF 
HEALTH INFORMATION? 
By taking part in this research study, your personal health information, as well as information 


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that directly identifies you, may be used and disclosed.  Information that identifies you includes, 
but is not limited to, such things as your name, address, telephone number, and date of birth.   
 
Your personal health information includes all information about you which is collected or 
created during the study for research purposes. It also includes your personal health information 
that is related to this study and that is maintained in your medical records at this institution and at 
other places such as other hospitals and clinics where you may have received  
medical care.  Examples of your personal health information include your health history, your 
family health history, how you respond to study activities or procedures, laboratory and other test 
results, medical images, photographs/videotapes/audiotapes and information from study visits, 
phone calls, surveys, and physical examinations. 
 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.   
 
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA), the Department of Health and Human Services 
(DHHS) and similar agencies in other countries. 
  
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable. 
 
If this research study involves the treatment or diagnosis of a medical condition, then 
information collected or created as part of the study may be placed in your medical record and 
discussed with individuals caring for you who are not part of the study. This will help in 
providing you with appropriate medical care.  In addition, all or part of your research related 
health information may be used or disclosed for treatment, payment, or healthcare operations 
purposes related to providing you with medical care. 
 
When you sign this consent and authorization form you authorize or give permission for the use 
of your health information as described in the consent form. You can revoke or take away your 
authorization to use and disclose your health information at any time. You do this by sending a 
written notice to the investigator in charge of the study at the following address: 
 


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WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00003943 
Meeting Date Approved 9/28/2011 
Version Valid Until: 9/27/2012 
James C. Eisenach, MD 
Wake Forest University School of Medicine 
Department of Anesthesiology 
Winston-Salem, NC  27157-1009 
 
If you withdraw your authorization you will not be able to be in this study. If you withdraw your  
authorization, no new health information that identifies you will be gathered after that date. Your 
health information that has already been gathered may still be used and disclosed to others. This 
would be done if it were necessary for the research to be reliable. You will not have access to 
your health information that is included in the research study records until the end of the study. 
 
Your participation is confidential and although the results of the study will be published in a 
scientific journal, no individuals, including yourself, will be identified.  The records for this 
study will be kept private to the extent permitted by applicable law. Representatives of the study 
staff, the WFUSM Institutional Review Boards, may however, review your records for this 
study.   
 
This authorization is valid for six years or five years after the completion of the study, whichever 
is longer. 
 
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study.  
 
WHAT ARE THE COSTS? 
There are no costs to you for taking part in this study. All the study costs, including any study 
medications and procedures related directly to the study, will be paid for by the study. Costs for 
your regular medical care, which are not related to this study, will be your own responsibility. 
 
 
WILL YOU BE PAID FOR PARTICIPATING? 
You will be paid $150.00 if you complete all the scheduled study visits. There is no payment 
given for the screening (first) visit.  The remaining four visits are paid at $25.00 each and an 
additional $50.00 for answering the questions on the PDA for the full length of study and 
returning the equipment at the end of the study. 
 
If you withdraw for any reason from the study before completion you will be paid according to 
the schedule above for visits you completed. 
 
To receive payment, you must provide your social security number, name and address so that we 
can comply with IRS (Internal Revenue Service) reporting requirements.  When payments are 
reported to the IRS we do not let them know what the payment is for, only that you have been 
paid.  If you do not wish to provide this information you can still take part in this study but you 
will not be paid. 


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WFU School of Medicine 
Institutional Review Board 
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Version Valid Until: 9/27/2012 
 
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur. 
 
WHO IS SPONSORING THIS STUDY? 
This study is being sponsored by the National Institutes of Health. The sponsor is providing 
money or other support to Wake Forest University Health Sciences to help conduct this study. 
The researchers do not, however, hold a direct financial interest in the sponsor or the product 
being studied. 
 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY? 
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at (336) 716-3467. 
 
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Dr. James C. Eisenach at (336) 716-4498. 
 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT? 
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because, you had an unexpected reaction, or because the entire study 
has been stopped. 
 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
You have the right to ask questions concerning this study at any time, and you are urged to do so.  
If you have any questions concerning this study or have questions concerning a research related 


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injury, please contact Dr. James C. Eisenach at (336) 716-4498 for further information about this 
study. After hours you may page the study coordinator, Regina Curry, RN at (336) 806-9496 and 
ask that she contact Dr. Eisenach to return your call. 
 
You may also contact the Chairman of the Institutional Review Board at (336-716-4542) at 
Wake Forest University School of Medicine for any questions about your rights as research 
participant. 
 
You will be given a signed copy of this consent form.  
 
 
SIGNATURES 
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence. 
 
 
 
_____________________________________________________  
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 Subject Name (Printed)                                                                                  Date/Time 
_____________________________________________________  
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 Subject Signature                                                                                            Date/Time               
 
_____________________________________________________  
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 Person Obtaining Consent                                                                                Date/Time