Three Way Interaction Between Gabapentin, Duloxetine, and Donepezil in Patients With Diabetic Neuropathy
Phase: PHASE4
Conditions: Diabetic Neuropathic Pain, Chronic Low Back Pain
Sponsor: Wake Forest University

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 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 2 of 11 
 
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 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 3 of 11 
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 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 4 of 11 
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 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 5 of 11 
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 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 6 of 11 
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 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 7 of 11 
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 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 8 of 11 
(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:  

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 9 of 11 
 
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. 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 10 of 11 
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. 

3-way interaction 
James C. Eisenach, M.D. 
Anesthesiology 
 
Version VI 
February 10, 2009 
Page 11 of 11 
 
 
 
 
 
 
 
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.