Pain and Function After Orthopedic Surgery
Conditions: Chronic Pain
Sponsor: Wake Forest University

Protocol version: 7/23/2012 
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Study Title: Pain and function after orthopedic surgery 
 
Principal Investigator, Co-investigator(s): James C Eisenach, MD (PI), Bob Coghill, PhD 
(Co-I), Tim Houle, PhD (Co-I), Andrew Koman, MD (Co-I), Scott Miller, MD (Co-I) 
 
Sponsor or funding source: Anesthesiology Department and Neurobiology and Anatomy 
Department 
 
Background, Rationale and Context 
 
Chronic Pain After Surgery 
 
Primary indications for major joint surgery include limited joint function and pain.  
Although joint replacement or repair surgery is usually remarkably effective, in some cases pain 
and function are worse or not improved after surgery.  Chronic pain after some surgical 
procedures, e.g., phantom limb pain after extremity amputation, has been long recognized, but 
more recent investigations suggest that chronic pain after physical injury including that of major 
surgery is not uncommon.  The purpose of this study is to provide preliminary data for a 
Program Project Grant to the National Institutes of Health to examine specific hypotheses 
regarding identifying patients at risk for chronic pain after surgery and probing mechanisms 
which may be manipulated to decrease this risk. 
 
Chronic pain after surgery is typically defined as pain outlasting the normal healing 
process from uncomplicated surgery.  Although there is some disagreement regarding the time 
normal healing is required, most investigators consider pain beyond 2 months, and certainly 
beyond 6 months after surgery as abnormal.  As such, patients with chest wall pain 2 months 
after augmentation mammoplasty have a nearly 18-fold relative risk of having chest wall pain 4 
years later compared with those without pain at 2 months (1). 
 
The incidence of chronic pain after surgery ranges from 10-50% (2).  After breast 
surgery for cancer, nearly half of those with chronic chest wall pain after surgery rate it as 
moderate to severe and seek treatment for it (3).  Given that there are nearly 250 million major 
surgical procedures performed annually on a global basis, the problem of chronic pain after 
surgery is thus a major public health problem. 
 
The etiology of chronic pain after surgery is unknown.  Since most patients with chronic 
pain after surgery exhibit symptoms consistent with neuropathic pain, it is assumed that 
peripheral nerve injury, either to small nerve branches or larger, peripheral nerves, may be an 
important cause.  Alternatively, primary afferent nerve traffic after surgery to the spinal cord may 
elicit plastic changes in pain transmission and procession in the spinal cord and supraspinally 
which underlie chronic neuropathic pain.  In animal models of chronic pain after surgery, many 
such plastic changes can be demonstrated. 
 
Descending modulation  
 
The central hypothesis for the Program Project Grant application for which this is a 
preliminary study is that descending modulation of pain processing to the spinal cord plays an 
essential role in determining whether pain after surgery resolves or continues to become 
chronic.  This follows from several observations and builds on the concept that the perception of 
pain after a peripheral noxious stimulus is not constant, but can be powerfully decreased or 
increased by sub-cortical neurons in the brainstem which project to the spinal cord and alter 
pain neurotransmission.  Powerful pain inhibition has long been recognized in the early period 
after major trauma in military or civilian life, with temporary absence of pain despite major injury 
that can last from minutes to hours.  Similarly, experimental pain can be amplified acutely by 
enforcing anticipation of pain, and several changes in the spinal cord which amplify pain after 
peripheral trauma are depending on descending facilitation pathways. 

Protocol version: 7/23/2012 
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We have spent 25 years examining the role and mechanisms of one of the major 
descending pain inhibitory pathways, comprised of cells in the pontine locus coeruleus and 
adjacent nuclei which project to and release norepinephrine in the spinal cord.  This pathway is 
activated by traditional analgesics such as morphine as well as those used primarily in chronic 
pain settings such as gabapentin, or can be amplified by other drugs used to treat chronic pain, 
such as monoamine reuptake inhibitors.  More recently, we have shown in animals that 
selective destruction of this descending noradrenergic system prior to surgery results in greatly 
prolonged or absent recovery in pain behaviors after surgery, suggesting that this system is 
essential for normal recovery and prevention of chronic pain after injury.  As part of the Program 
Project Grant application we will explore in detail the mechanisms by which this pathway is 
regulated and by which it protects the individual from chronic pain after injury. 
 
Descending inhibition of pain can be temporarily engaged in normal humans by applying 
a noxious stimulus.  This concept of ‘pain inhibiting pain’ is most easily demonstrated by placing 
a foot in a mildly noxious cold water bath and testing for pain perception on another extremity 
(4).  The noxious stimulus applied to the foot results in reduction in pain perceived by an 
experimental hot stimulus to the arm.  In humans this effect is blocked by naloxone, indicating a 
role for endogenous opioids (5).  In animals, this effect is blocked by naloxone administered to 
several brainstem sites and by spinal injection of a noradrenergic receptor antagonist, indicating 
engagement of descending noradrenergic inhibition. 
 
There is wide inter-individual variability in the degree to which pain inhibits pain using 
this experimental method.  Since we believe that activating descending inhibition is essential to 
normal recovery of pain after surgery, it is not surprising that the degree to which this system 
can be demonstrated experimentally using this pain-inhibits-pain test correlates strongly with the 
risk of chronic pain after surgery (6). 
 
Stress and reward 
 
In addition to surgical factors (specific procedure and likelihood of nerve injury) and 
biologic factors (including ability to engage descending modulation), several psychosocial 
factors are associated with an increased risk of chronic pain after surgery.  Especially prominent 
and consistent factors associated with increased risk are pre-existing depression, anxiety, fear 
of pain, and catastrophizing.  Our central hypothesis is that these cognitive aspects reflect brain 
connectivity and patterns of activity which gate pain perception.  Several lines of converging 
evidence indicate important roles for medial prefrontal cortex, amygdala and basal ganglia in 
processing noxious stimuli within the overall context of the internal and external environment.   
 
This subconscious processing can significantly alter pain processing and the normal 
resolution of pain after injury.  For example, we recently observed a remarkably low incidence of 
chronic pain after childbirth, including cesarean delivery.  Similarly, in animals we showed that 
the immediate post-delivery period is associated with protection from chronic pain from 
peripheral nerve injury and that this protection was lost when oxytocin receptors in the spinal 
cord were blocked pharmacologically.  Centrally released oxytocin has long been known to 
enhance social interactions, bonding, and trust, while reducing fear and anxiety.  In addition, we 
propose that individuals or populations, such as new mothers, with increased oxytocin signaling 
are protected from chronic pain after physical injury.  Initial studies in our laboratory indicate that 
oxytocin does this by increasing descending noradrenergic inhibition and by decreasing 
descending facilitation. 
 
In contrast to reduced pain responses and positive psycho-social engagement 
encouraged by oxytocin, high levels of psycho-social stress produce nearly opposite effects.  As 
such, a model of high stress in rodents induced by repeated social defeat results in anxiety 
behavior, exaggerated responses to noxious stimuli, and evidence of plasticity associated with 
chronic pain (7).  Within the laboratory studies of our Program Project Grant application will be 
manipulation of environmental and neurohormonal factors to understand the link between higher 

Protocol version: 7/23/2012 
3 
ordering cognitive function and chronic pain after injury.  The presumed link includes 
engagement of descending noradrenergic pathways.  We will propose parallel clinical trials to 
examine the role of psychosocial factors on resolution of pain after surgery. 
 
 
Context of this IRB application 
 
As noted above, chronic pain after surgery is a major health problem and we have 
minimal understanding of whether cognitive and provocative pain testing factors associated with 
increased risk of this problem are mere associations or causations.  We propose to test, within 
the context of a multi-investigator NIH application, whether chronic pain after surgery is caused 
by an inadequate response from descending inhibition and whether cognitive and psychosocial 
factors determine whether pain after surgery resolves or becomes chronic by controlling 
descending inhibitory tone. 
 
We will submit a Program Project Grant application for the October, 2011 deadline and 
the purpose of this IRB application is to acquire preliminary data to demonstrate feasibility and 
allow an accurate power analysis for the size of the proposed study within that grant application. 
 
 
 
Objectives 
The objectives of this pilot effort are:  
1) To demonstrate the feasibility of conducting this protocol in this clinical population. The 
execution of this study will allow us to identify expected enrollment rates, patient  drop-out rates, 
and other threats to the accurate assessment of the course of pain after major joint surgery. 
 
2) To estimate the individual variability in pain trajectories over time and to obtain effect size 
estimates for factors that predict pain trajectory. 
 
3) To demonstrate feasibility of providing a pre-surgical teaching intervention in this clinical 
population.  
 
 
Methods and Measures 
 
Design  
The proposed study is a prospective longitudinal observational study. Patients who are 
undergoing elective orthopedic surgery: unicompartmental knee replacement, a total knee 
replacement or total hip replacement will be approached and asked to provide consent to 
participate in 6 months of observation after their surgery. During this time, participants will not 
alter their usual treatment in any way (i.e., no treatment algorithms will be altered for this study), 
but will complete diaries and survey instruments at numerous intervals. 
 
Setting  
 
The study will be conducted on patients scheduled for major joint orthopedic surgery at 
Wake Forest University Health Sciences WFUHS.  Informed consent and pre-surgical surveys 
and CBT Intervention will be performed during the preoperative visit in the Joint Replacement 
Education Conference Room, Preoperative Assessment Clinic or in the Orthopedic Clinic. 
Perioperative care will be provided at the surgical and post-surgical areas of WFUHS. 
 
Subjects selection criteria 
 
 
Inclusion Criteria 

Protocol version: 7/23/2012 
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Adult patients scheduled for elective unicompartmental, total knee replacement, or total 
hip replacement surgery, will be included.  Patients will be American Society of 
Anesthesiologists physical status 1, 2, or 3. 
 
 
Exclusion Criteria 
We will exclude patients who do not understand English (subjects must be able to read 
English to answer the questionnaires. The questionnaires are not available in multiple 
languages), those who are pregnant or within 1 year of childbirth, those with Raynaud’s 
phenomena of the foot, and those with neuropathy of the lower extremities with loss of 
temperature sensation. 
 
 
Sample Size 
The proposed pilot study aims at identifying effect size estimates and indicators of 
feasibility. As such, the proposed sample size is not intended to provide definitive 
estimates of the hypotheses underlying the research. Instead, we propose to enroll N = 
75 participants to obtain estimates of drop-out rates (this sample size will allow 95% 
confidence interval precision of +- 8.2% assuming a 25% drop-out rate)  as well as initial 
estimates of effect sizes for the predictors in the study. 
   
Interventions and Interactions  
 
 
All patients will complete written informed consent.  In addition to review of medical 
history, indication for major joint surgery and current joint function will be recorded.  
 
The following questionnaires will be completed: 
 
Daily Stress Inventory (DSI, Brantley et al., 1987; 58 items) 
 
 
Catastrophizing Scale of the Coping Strategies Questionnaire (CATS, 7 items) 
 
McGill Pain Questionnaire-SF (MPQ-SF) 
 
 
 
 
 
 
 
 
 
 
Pre-surgical Intervention: 
 
After completion of baseline questionnaires (MPQ-SF, DSI, CATS) the Brief CBT 
Intervention will be viewed by the subject. Upon completion of the presentation, the CATS 
questionnaire will be administered again.  The subject will receive a packet containing “The 
Power of the Mind,” they will be asked to read this information and complete the exercise at the 
end of the packet.  The study staff will call the subject one week after the initial meeting and ask 
if they have read the packet and will also have the subject to complete the CATS questionnaire 
again. A postage paid, addressed envelope will be provided for the subject to return the 
questionnaires to the study team. The questionnaires will be de-identified and only contain 
subject initials and study identification number. 

Protocol version: 7/23/2012 
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At Home Diary Assessments 
 
The subject will be given a notebook with paper questionnaires and instructions on how 
to complete the questionnaires per the schedule below.   
All participants will complete the 
assessments in a sequence using one of several methods: 
A. Inpatient evaluation (surgery to discharge): Nursing staff will inquire about the patients pain 
levels using standard of care methods and assessment tools (e.g., numerical rating scale 0 – 
10).   
B. Ecological Momentary assessment (discharge to day 14): The subject will complete the 
questionnaires in the morning and in the evening. 
C. Once daily (day 15 to day 28): The patient is instructed to complete a diary entry at the end 
of their day, just prior to going to sleep. 
D. Once weekly (day 29 to day 85): The patient will be called at their home and participate in a 
brief interview. 
E. Once monthly (day 86 to day 168): The patient will be called at their home and participate in 
a brief interview once each month. 
Each of the assessments will only require about 5 to 10 minutes to complete.  At each of the at 
home assessments the McGill Pain Questionnaire-SF will be administered. 
In addition, information from the postoperative care from the orthopedic surgery division will be 
recorded, including range of joint motion and functional limitations, if any, at the times of routine 
postoperative clinic visits.   
 
 
Table 1. A summary of the data collection procedures for the observational study 
 
Assessment 
Type 
Time 
(Days) 
Questionnaires Joint 
Sensory 
Testing 
Thermal 
Pain 
Testing 
DNIC 
Protocol 
Diary type 
Visit 1  
-14 to 0 
X 
X 
X 
X 
NA 
Post-op 
0 to 3 
 
 
 
 
NA 
Home 
4 to 14 
 
 
 
 
Ecological 
Momentary 
Assessment 
Home 
15 to 28 
 
 
 
 
Once-daily 
Home 
29 to 85 
 
 
 
 
Weekly 
Home 
86 to 
168 
 
 
 
 
Monthly 
 
 
 
 
 
 
 
 
 
Outcome Measure(s) 
 
The primary outcome measure for this study is self-reported pain intensity. To obtain 
estimates of pain intensity, we will use the McGill Pain Questionnaire - Short Form (MPQ). This 
instrument has been extensively used to assess pain in a wide variety of settings, and is 
uniquely suited to our present study in that the items can be completed while in a post-operative 
setting as well as a daily diary setting.   

Protocol version: 7/23/2012 
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Analytical Plan  
The proposed pilot study aims at identifying effect size estimates and indicators of 
feasibility. As such, the analytical plan is primarily descriptive in nature. Careful attention will be 
given to missing data due to any reason, participant withdrawal, and evidence of corrupted or 
invalid assessments. These threats to data collection will be itemized and descriptive statistics 
will be used to summarize the rates and expected proportions (with 95% confidence intervals) of 
measurements that may be lost due to any reason.  
To estimate individual variability in the trajectory of pain over time (i.e., healing and 
diminishing pain reports), and predictors of that trajectory, hierarchical linear modeling 
(Raudenbush & Bryk, 2002) will be used.  The application of HLM in individual change data is 
well suited for the examination of post surgery pain.  Briefly, change trajectories are created for 
each participant. Because of the nature of the expected change, the trajectories will be modeled 
using an intercept, slope, and quadratic term.  The intercept is coded to represent the baseline 
level of the pain score (day of surgery).  The slope estimates the linear change over time and 
represents the increase or decrease in the variable. Finally, the quadratic term estimates the 
acceleration or deceleration over time and reflects changes in the rate of change in pain 
reporting. 
 
To assess our specific hypotheses, we will first evaluate the appropriateness of a model 
that consisted of only intercept (starting value), time, and time-squared as first-level predictors.  
This first level model describes individual trajectories (change) across time. This model will be 
evaluated for fit, redundancy, and variability in the parameters and will be reduced to a linear 
change model if conditions indicate.  When a suitable first-level model is developed, and if there 
is significant variation across participants in either the intercept or change parameters, a second 
level model will be specified. The second level model will examine the impact of the 
questionnaires and baseline sensory testing on the trajectories (i.e., linear and quadratic 
components of the first level model). In all cases, the model coefficients and their standard 
errors will be of primary interest to inform out later, definitive study.    
 
 
Risks 
Taking part in this research study may involve subject’s providing information that they consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
research related information safe. 
 
 
Human Subjects Protection  
 
Subject Recruitment Methods 
Patients scheduled for unicompartmental knee,  total knee replacement, or total hip 
replacement surgery at WFUHS will be contacted by telephone by our research nurse at least 2 
days before surgery.  All adult patients scheduled for surgery within the inclusion criteria 
discussed above will be considered as eligible, regardless of sex, race, or ethnicity.  Privacy will 
be protected by safekeeping and then destruction of surgical posting lists obtained from the 
Division of Orthopedic Surgery and by the maintenance of all records on password protected 
computers. 
 
Patient name, age, telephone number, surgical indication, date and procedure 
scheduled for major joint surgery will be collected to identify and contact potential participants.  

Protocol version: 7/23/2012 
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This information will be kept on print out in a locked location or on a WFUHS password 
protected computer.  Print out will be shredded and file containing the name will be deleted 
within 24 hr of declining to participate. 
 
 
Informed Consent  
Signed informed consent will be obtained from each subject.  Subjects will be recruited from the 
Orthopaedic Clinic. The staff in the Orthopaedic Clinic may call the study coordinator to see 
patients in the clinic for discussion of the research study and patients may also be contacted by 
telephone and the study discussed with them. However, the study coordinator   will obtain the 
informed consent from the subject in the Orthopedic Clinic, Preoperative Assessment Clinic or 
in the Joint Replacement Education session.   
 
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 
directly identify subjects, and maintaining all study information in a secure manner.  To help 
ensure subject privacy and confidentiality, only a unique study identifier will appear on the data 
collection form.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a linkage file, store separately from the data.  The linkage file will 
be kept secure, with access limited to designated study personnel.  Following data collection 
subject identifying information will be destroyed three years after closure of the study consistent 
with data validation and study design, producing an anonymous analytical data set.  Data 
access will be limited to study staff.  Data and records will be kept locked and secured, with any 
computer data password protected.  No reference to any individual participant will appear in 
reports, presentations, or publications that may arise from the study. 
 
 
 
 
 
 
Data and Safety Monitoring  
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study 
staff. Because this is an observational study, with minimal risk, no data and safety monitoring 
board will be convened. However, threats to participants’ confidentiality will be minimized using 
the following methods. First, the collected data will be stored on University networked, password 
protected computers. The databases will be created such that only a patient ID number 
identifies participant records, and that ID will be linked to actual patients in a separate file that 
itself is password protected on the PIs computer. The diary information, recorded at the 
participant’s home will not contain any protected health information, and will only be linked to 
the participant through internal database keys.  
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB and sponsor or appropriate government agency if appropriate. 
 
 
 

Protocol version: 7/23/2012 
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