Clinical trial NCT01743976
Conditions: Neuropathic Pain
Keywords: neuropathic pain diabetic neuropathy neuropathic pain after back surgery
Sponsor: Wake Forest University
Start date: 2012-12-01; Completion date: 2013-10-23
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Based on laboratory studies, donepezil will improve pain relief more than placebo in patients with chronic neuropathic pain who are currently taking gabapentin or pregabalin.

Detailed description:
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.

Arms: arm 1: donepezil 5 mg every day arm 2: Placebo (sugar pill) every day
Interventions: intervention 1: Donepezil intervention 2: Placebo
Intervention descriptions: intervention 1: donepezil 5 mg once daily for 6 weeks intervention 2: placebo or sugar pill will be taken once daily for 6 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012 
Page 1 of 10 
NCT01743976 
Donepezil Compared to Placebo in  
Patients With Chronic Neuropathic Pain 
Protocol ID: IRB00022107 


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012 
Page 2 of 10 
Donepezil compared to placebo in patients with chronic neuropathic pain 
Investigators: James C. Eisenach, M.D., Tim Houle, Ph.D., Regina Curry, R.N. 
Hypothesis: Based on laboratory studies, donepezil will improve pain relief more than 
placebo in patients with chronic neuropathic pain who are currently taking gabapentin or 
pregabalin. 
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.   
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.   


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012 
Page 3 of 10 
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, We 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 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 33 patients with diabetic neuropathic pain and predominant 
neuropathic pain following back surgery will be recruited from the Wake Forest School 
of Medicine; surrounding Piedmont Triad community.   
1. Diagnosis of diabetic neuropathy or failed back syndrome with neuropathic symptoms
2. Age 18-80
3. Taking a stable dose of gabapentin or pregabalin
4. Subjects will be able to continue their other prescribed medications maintaining a
stable dose. 
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


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012 
Page 4 of 10 
2. Allergy to   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. Uncontrolled narrow-angle glaucoma
9. Currently being treatment with thioridazine (Mellaril)
10. Patients taking opioids will be excluded if they are taking a dosage that
exceeds an equivalent of 30 mg of morphine per day 
11. Patients taking more than one regular (not rescue) medication for pain
12. Patients taking donepezil for dementia
13. 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 Clinical 
Research Unit (CRU) at Wake Forest 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, donepezil, 5 mg qd, or placebo for the next 
6 weeks.  At the end of the 6 week study drug administration, patients will return to CRU 
and data from the PDA downloaded and checked for compliance.    Their experimental 
treatment (donepezil or placebo,) will then be stopped at this time with daily PDA entry 
to be continued for two weeks. 
Additionally we will offer the following options for study subjects for data collection: 


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012  
Page 5 of 10 
paper and pencil questionnaires, a secure electronic database via the internet (Red Cap) or 
by twice daily phone calls from the study staff.  We feel these options will increase 
compliance for subjects in completing the questionnaires. 
Experimental Design:  
The study will be conducted over a period of 10 weeks; consisting of baseline (2 
weeks), randomized drug assignment (6 weeks), and washout (2 weeks).  During this 
time patients will make 4 visits to the CRU (screening visit, drug randomization visit, 8 
week and 10 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 or they will be trained on 
entering the data into the RedCap system if they choose this method. The subject may 
also elect to complete these forms in paper format if they are not comfortable with the 
PDA or if they have difficultly visualizing the PDA.  The subject will return for the 
randomization visit to the CRU and data will be downloaded and checked for 
compliance.  Patients will be randomized, using a balanced double blind design, to 
receive donepezil, 5 mg qd, or placebo for the next 6 weeks.  
At the end of week 8, subjects will return to the CRU and data from the PDA 
downloaded and checked for compliance.  At the end of week 10, patients will return to 
the CRU and data from the PDA (if this option was used for data collection) downloaded 
and checked for compliance.   
Screening Randomization
Visit 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
10 
Visit 
 1 
Visit 
2 
Visit 
3 
Visit 4 
Informed Consent 
X 
Urine Pregnancy 
X 


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
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 
Version  
November 19, 2012  
Page 6 of 10 
Test 
Pain Questionnaires 
X 
Physical Exam 
X 
PDA/Questionnaires 
Instructions 
X 
PDA Download 
X 
X 
X 
Randomization 
X 
Blinded Study Med 
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 
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. 


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012  
Page 7 of 10 
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 “washout”) 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).  
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 
(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 


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012  
Page 8 of 10 
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 2 = N = 30) 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 = 30 participants have 
taken at least one dose of study medication). Further, the 10 week trial, with two 
observations per day provides a sufficient number of observations  to incorporate the 
interrupted time-series analysis strategy for the secondary analyses (5). 
Adverse Events/Side Effects: 
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 


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
Version  
November 19, 2012  
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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. 
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.    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 and the questionnaires will not have personal 
identifiers on them. 
Data Safety Monitoring Plan 


Donepezil vs placebo 
James C. Eisenach, M.D. 
Anesthesiology 
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November 19, 2012  
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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. 
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: 
9/14/2015 
NCT01743976 
Donepezil Compared to Placebo in  
Patients With Chronic Neuropathic Pain 
Protocol ID: IRB00022107 


Version 
May 16, 2013
Page 1 of 9
Department/Section of Anesthesiology
Donepezil compared to placebo in patients with diabetic neuropathy and 
neuropathic back pain
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 Clinical Research Unit (CRU) at Wake Forest Baptist Medical Center. There will 
be approximately thirty-three subjects involved in this research project.  The length of 
participation will last 10 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. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00022107
Meeting Date Approved 9/14/2015          
Version Valid Until: 9/13/2016


Version 
May 16, 2013
Page 2 of 9
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to test whether donepezil (used for treatment of 
Alzheimer’s disease) will have any effect (good or bad) on your current pain. Donepezil is an 
FDA approved drug. Donepezil is considered to be investigational in this study. 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 donepezil 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 33 people included in this study.  Subjects will be assigned to one of two 
groups. 
Group 1: Will receive donepezil 5mg.  
Group 2: 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.  
WHAT IS INVOLVED IN THE STUDY?
The study lasts 10 weeks. We ask that you do not add any new medications or receive injections 
to treat your pain during this 10 week study period. You will have four visits to the CRU. 
Week 0: Begin data collection
Week 2: Begin randomized study medication and continues data collection
Week 8: Complete randomized study medication and continues data collection
Week 10: Complete data collection and all study requirements
CRU  visit1:
• 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.  
• 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 
morning and evening) to answer the questions.  These questions are about your pain. If you do 
not feel comfortable using the PDA we will provide you with the questionnaires on paper and 
place them in a binder for you. You also may choose to complete the questionnaires two times 
each day by using the internet to access our secure database and answering the questions or we 
will also give you the option for us to call you two times a day and complete the questionnaires 
by telephone. This visit will take about four hours.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00022107
Meeting Date Approved 9/14/2015          
Version Valid Until: 9/13/2016


Version 
May 16, 2013
Page 3 of 9
CRU visit 2: 
• We will connect your PDA to a computer and check if you have been answering the questions 
twice a day or we will collect the paper questionnaires.  We will do this at every visit.
• If you are still eligible for the study, you will be randomized into one of the two 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 two 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, complete the paper 
questionnaires answer the questions using our secure electronic database,  or by telephone 
• This visit will take about two hours.
CRU Visit 3: You will bring your blinded drug and PDA (or your paper questionnaires) so we 
can check to make sure you have been taking the study drug properly and answering all your 
questions. This will complete your study medication treatment period. 
• You will continue using your PDA every morning and evening, complete the paper 
questionnaires answer the questions using our secure electronic database,  or by telephone 
• This visit will take about two hours.
CRU Visit 4: 
• You will bring your PDA (or paper questionnaires) so we can check to make sure you have 
answered all your questions.  
• You will return the PDA (or paper questionnaires).  This visit will take about two hours.
• You will return any unused study medication at this visit.
HOW LONG WILL I BE IN THE STUDY?
You will have four study visits over a 10 week period. Your study participation will be complete 
after the fourth visit to the CRU.
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.
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 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00022107
Meeting Date Approved 9/14/2015          
Version Valid Until: 9/13/2016


Version 
May 16, 2013
Page 4 of 9
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.
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.
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.  
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00022107
Meeting Date Approved 9/14/2015          
Version Valid Until: 9/13/2016


Version 
May 16, 2013
Page 5 of 9
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. There is the possibility that your physician 
would prescribe donepezil to you to help with your pain. 
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 
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 
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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:
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. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time.
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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 three visits are paid at $25.00 each and an 
additional $75.00 for answering the questions on the PDA for the full length of study and 
returning the equipment or questionnaires at the end of the study.
To assist you with the cost of fuel for the required study visits we will also give you a $25 gas 
card according to the mileage listed below:
(1) If your total study related travel mileage (calculated from your home address) is 250 miles or 
less you will be given a $25 gas card at the end of study visit 4.
(2) If your total study related travel mileage (calculated from your home address) is greater than 
250 miles you will be given a $25 gas card at the end of study visit 2 and at the end of study visit 
4.
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.
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 
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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 
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. 
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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.
_____________________________________________________
______________
Subject Name (Printed)                                                                                  Date/Time
_____________________________________________________
______________     
Subject Signature                                                                                            Date/Time              
_____________________________________________________
______________
Person Obtaining Consent                                                                                Date/Time
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00022107
Meeting Date Approved 9/14/2015          
Version Valid Until: 9/13/2016