Predicting, Understanding, and Speeding Recovery After Total Knee Arthroplasty
Phase: PHASE4
Conditions: Pain, Total Knee Replacement, Total Hip Replacement
Sponsor: Wake Forest University Health Sciences

Official Title:  A Multi-Center Study: Predicting, Understanding and Speeding Recovery after Total Joint 
Replacement
NCT02685735 
Date:  03/05/2020

Protocol version: 3/5/2020
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Study Title: Predicting, Understanding, and Speeding Recovery after Total Joint Replacement 
Principal Investigator; Co-investigator(s): James C. Eisenach, M.D.; Timothy T. Houle, Ph.D., Jason 
Lang, M.D., Scott Miller, M.D.  
Sponsor or funding source: NIH 
Background, Rationale and Context 
Chronic pain after surgery is typically defined as pain outlasting the normal healing process from 
uncomplicated surgery, usually 2-6 months.  Given over 250 million major surgical procedures performed 
annually on a global basis and an incidence of chronic pain after surgery of 10-50% (Kehlet, 2006), the 
problem of chronic pain after surgery is clearly a major public health problem. Major surgery also results 
in acute physical disability which is especially important after procedures for which the primary 
indication is to improve or remove disability, exemplified by major total joint replacement surgery. We 
chose to study total knee arthroplasty (TKA) and total hip arthroplasty (THA) in this NIH grant 
application for two reasons.  First, TKA is a commonly performed surgery to reduce pain and improve 
function,  and 3.5 million TKAs are predicted to be performed each year in the US by 2030 (Kurtz, 2007).  
Second, although most patients show improved joint range of motion from this surgery, approximately 
40% of patients fail to improve function after TKA as assessed by validated measures of minimally 
clinical important improvement (MCII), and 10-20% are left with chronic, moderate to severe pain 
(Maxwell, 2014; Singh, 2014a).  
Critical barriers to progress addressed by this study. These are fourfold: 
1. Focus on dichotomous outcomes. Clinical and preclinical
studies on recovery from surgery utilize dichotomous outcomes, 
which makes no biological sense.  Recovery after injury is a dynamic 
process, and the very few longitudinal, prospective studies in this area 
show that the incidence of this dichotomous outcome continues to 
decline for years following surgery (Kaasa, 2010).Thus, choosing an 
arbitrary time to define chronic pain or disability after surgery tells us 
little about the path upon which patient are recovering and when they 
will recover.  The cartoon in Figure 1 depicts the problem.  The 
incidence of “chronic” pain or disability changes over time and 
predictive models based on disparate times are likely to be 
inconsistent and potentially misleading.  The subject in orange in 
Figure 1, for example, experienced considerably more pain, disability, 
and possible risk for opioid misuse, than the one in blue, but both are 
lumped as “no chronic pain” at 12 months. We do not argue that
dichotomous outcomes at fixed times after surgery are worthless as 
primary outcome measures for interventional trials, but beyond this 
we believe they represent barriers to understanding and progress.   
Clearer definition of normal time course of improvement in 
pain and other patient-centered aspects of recovery could significantly 
impact surgical decisions regarding candidates for surgery and 
managing expectations (Losina, 2012).  Previous efforts to define 
trajectory of recovery from pain and disability were limited to a few 
days after surgery (Brewer, 2007; Chapman, 2011; Althaus, 2014), 
although one study recently extended this to 45 days (Gaudilliere, 
2014).  To demonstrate feasibility of high density time sampling for 
Figure 1: Time course of recovery 
from pain or disability in 5 
hypothetical patients after surgery 
Figure 2: A) Modeled time course of 
recovery from pain, B) latent classes 
of recovery, C) and time course for 
recovery in activity 

Protocol version: 3/5/2020 
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months after surgery we recorded frequent pain assessments in 31 patients after lower extremity total joint 
arthroplasty and 155 women after cesarean delivery. The time course of daily pain intensity was best 
modeled to a log of time function in both cases and, as expected, worst daily pain was initially slightly 
less intense and resolved considerably more rapidly after cesarean delivery than arthroplasty (Figure 2A).  
Latent class analysis of the cesarean delivery group yielded 3 distinct patterns of recovery (Figure 2B), 
although this is an ongoing study and 550 total subjects will be required to allow adequate power for a 
stable latent class analysis.   
 
 
2. Focus on pain in isolation.  Major surgery induces dysfunction in many patient centered 
domains, including pain, physical disability, cognitive dysfunction, and risk of prescription opioid misuse, 
which has been linked to impulsivity (Marino, 2013).  For many surgical procedures, and certainly for 
TKA, patients choose surgery in the hope of less pain and better quality of life.  Yet most studies focus on 
one or at most two outcomes, most commonly components rather than integrated patient centered 
outcomes.  We will repeatedly apply the simple, 12-question World Health Organization Disability 
Assessment (WHODAS) 2.0, recently validated in postoperative patients to define disability-free survival 
(Shulman, 2015) in order to define the trajectory of this patient-centered, integrated outcome.  We will 
also frequently quantify the important components of pain (feasibility shown in Figure 2A and B) and 
physical activity using Fitbit™ accelerometers (feasibility shown in Figure 2C) in order to define 
trajectory of recovery in these domains. We will also repeatedly assess executive function and impulsivity 
(along with daily opioid use) to test novel hypotheses in parallel with lab projects in this NIH Program 
Project (P01) application which assess these constructs.  Finally, we will examine the associations 
previously shown using dichotomous outcomes between known risk factors for individuals with chronic 
pain and dysfunction after surgery (Scott, 2010; Wylde, 2011; Rakel, 2012; Singh, 2014b) but applying 
growth curve analysis of recovery in pain, physical activity, and disability free survival.  
 
 
3. Lack of unifying testable hypothesis. Most critically, the field lacks a testable, mechanistic and 
actionable hypothesis of mechanisms of recovery from these impairments after surgery.  We provide one: 
 
 
The LC provides exclusive or near-exclusive innervation to the cortex, spinal cord, and several 
midbrain regions, where it provides important 
moderating input to areas involved in (among 
other things) pain, fear, attention, and 
impulsivity. LC neurons exhibit two modes of 
activity: spontaneous, tonic, low frequency firing 
(0.1-5 Hz) and phasic bursts (10-25 Hz) in 
response to external, sensory or cortical network 
stimuli.   
 
 
Two aspects of LC function determine its 
widespread modulatory effects. First, the 
interplay between tonic and phasic LC activity 
determines how the LC molds responses to the 
environment (Figure 3).  At low to moderate 
levels of tonic norepinephrine (NE) release from 
LC afferents, stimulation of α2-adrenoceptors 
increases gain across cortical circuits.  As 
opposed to amplification, which results in 
increased signals from all components of a 
Central hypothesis: Activity of the locus coeruleus (LC) at the time of and in response to surgical injury is 
a key determinant of speed of recovery across pain and other patient-centered domains. 
Figure 3: Conceptual relationship between tonic activity and 
level of arousal, attention, application of preferred cognitive 
style, and phasic response to stimuli. For domains 1-3 the 
curved text is meant to show an inverted U effect on these 
aspects of cognition. Drugs which increase tonic LC activity 
may exert opposite effects, depending on level of tonic 
activity (↑ if in  a  and ↓ if in  b ). 

Protocol version: 3/5/2020 
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complex circuit, increasing gain results in increased dominance of strong signals at the expense of weak 
signals, as recently demonstrated by fMRI in humans engaged in learning tasks (Eldar, 2013).  As tonic 
LC activity increases, so does level of alertness and the ability to focus on task (Figure 3, domains 1 and 
2) accompanied by the tendency to exploit the environment, which is viewed as predictable.  With higher 
tonic NE release, such as occurs under acute stress, these effects are degraded by activation of lower 
affinity α1- and β-adrenoceptors, resulting in hypervigilance, distraction (Suto, 2014), and tendency to 
explore the environment which is viewed as surprising / unpredictable (Gilzenrat, 2010; Jepma, 2011).  
Project 2 (a laboratory project in the P01 application) induces high tonic LC activity to test whether this 
results in beneficial effects to reduce impulsivity or detrimental effects to exaggerate attention deficits, 
and we will assess in humans the effect of tonic LC activity on these parameters following TKA. 
Impulsivity and attention are specifically regulated by the locus coeruleus, are relevant to 
postoperative cognitive dysfunction and potential opioid misuse, and are being studied in the 
preclinical arms of this NIH program project grant.   
 
 
Domains 3 and 4 are particularly relevant to pain.  For all but the lowest range of frequencies, 
increases in tonic LC neural firing frequency are accompanied by decreases in phasic bursts in response to 
salient stimuli (Figure 4A). Project 1 (a 
laboratory project in the P01 application) 
shows in rats that a manipulation which 
increases tonic LC activity reduces release 
of NE in the spinal cord in response to a 
noxious stimulus and reduces Conditioned 
Pain Modulation (CPM), a form of 
endogenous analgesia (Figure 4B).  In 
preliminary data, we observed that 
strength of CPM in 7 healthy volunteers 
(conditioning stimulus of foot in cool 
water with test stimulus of 5 sec 49⁰C 
stimulus to forearm (Nahman-Averbuch, 
2013)) was inversely related to resting 
pupil diameter in a constant luminosity, 
darkened environment as a proxy for tonic 
LC activity (Figure 4C). In animals, CPM 
is dependent on LC→spinal noradrenergic 
signaling, and in both animals and 
humans, low CPM is associated with a greater risk of chronic pain after surgery (Yarnitsky, 2008; Peters, 
2015).  We will therefore test the hypothesis that resting pupil diameter, a stable trait in humans for long 
periods of time (Alnaes, 2014), predicts the strength of CPM and partially regulates the speed of recovery 
from pain after surgery.   
 
 
According to our central hypothesis, LC activity does not just regulate the time course of spinal 
sensitization and ascending nociceptive input, it also alters the pain experience, which results from 
supraspinal processing of this bottom-up signal (Figure 3, domain 3).  In humans, increased tonic LC 
activity results in stronger reliance on an individual’s preferred visual or semantic learning style  (Eldar, 
2013). To test whether a similar relationship exists in response to pain, 16 individuals with osteoarthritis 
of the hip or knee answered a series of questionnaires to place them on a catastrophizing↔optimism 
(C↔O) cognitive continuum, and resting pupil diameter was measured to infer tonic LC activity.  
Noxious heat stimuli were applied to the forearm using a Peltier-controlled thermode in 5-sec pulses, 
ranging from innocuous (41⁰C) to mildly or moderately noxious (47⁰C and 50⁰C, respectively).  A 
generalized estimating equation (GEE) analysis was applied to examine the repeated measurements of 
Figure 4: A) In this example an individual with higher tonic LC activity 
(Red) has less phasic response to a noxious stimulus than one with 
lower tonic activity (Green).  B) This yields fewer noxious stimulus-
induced action potentials (APs) of LC neurons with spinal projections 
(orange bars) resulting in lower CPM. C) As predicted by this 
hypothesis, CPM strength in 7 subjects was inversely related to 
resting pupil diameter, a validated measure of tonic LC activity in 
humans. 

Protocol version: 3/5/2020 
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temperature condition on C↔O dimension, and resting pupil diameter on pain reporting.  We anticipated 
that pain report would be affected by preferred style on the C↔O dimension, and this was observed at 
both 50⁰ and 47⁰ stimuli (Figure 5A; p=0.0007).  We anticipated that additional variance in pain report 
could be identified by the interaction between C↔O style and resting pupil diameter, and this was also 
observed (Figure 5B) although not significant in this underpowered small pilot sample.  As resting pupil 
diameter increased, pain report tended to increase or decrease depending on preferred style in the C↔O 
dimension. These data are consistent with tonic LC activity in this population residing in area b of Figure 
3, since increased tonic activity increased rigidity to apply the preferred style.  Tonic LC activity and 
hence this relationship may differ in the surgical population. 
 
 
This complex interaction between tonic LC activity and C↔O style on recovery from pain after 
surgery is important because its determinants (resting pupil diameter and cognitive assessment) can be 
easily measured and because it provides novel and testable predictions in the laboratory and clinic.  These 
preliminary data strongly support the use of pupillometry to infer tonic LC activity, as they also support 
the central hypothesis and the feasibility of testing it.  
 
 
4. Inability to target treatment to responders.  There are two critical barriers to identifying and 
targeting treatments to speed recovery from surgical injury.  First, surgical procedures utilized to study 
pain in rodents result in recovery within a few days (incision model of (Brennan, 1996)), or no recovery 
over many months (e.g., spinal nerve ligation (SNL) model of (Kim, 1992)). This P01 application utilizes 
partial SNL (Guan, 2010), a surgical procedure which resolves over 2 months, with recovery delayed if a 
negative affective phenotype is induced prior to injury.  Second, treatments based on theory or studies in 
rodents have been largely negative in the clinic, including prolonged regional blockade, gabapentinoids, 
clonidine, ketamine, and serotonin-NE reuptake inhibitors (SNRIs).  
This may reflect inability to identify responders. 
 
 
Without a testable and mechanistic rationale for treatment, 
understanding treatment failure and prospectively identifying responders 
are difficult.  This proposal will build on our central hypothesis, that the 
interaction between tonic LC activity and C↔O style regulates speed of 
recovery, to test whether responders to a drug which increases tonic LC 
activity can be predicted.  We chose gabapentin as that drug, based on 
animal and novel preliminary data in humans.  The osteoarthritis 
subjects described in Figure 4 were randomized to receive oral 
Figure 5. Ascending input from the spinal cord is conceptually filtered through a cognitive dimension which 
disperses pain experience, as supported by A) an observed relationship between predicted pain and 
preferred style on this C↔O dimension.  We hypothesize that further dispersion of pain occurs through 
filtering depending on degree of tonic LC activity, as supported by B) Spread of pain dependent on C↔O 
dimension increases as tonic LC activity (inferred by pupil diameter) increases (n=16 osteoarthritis 
patients).   
Figure 6: Change in pupil diameter 2 hr 
after oral treatment (bars are median) 

Protocol version: 3/5/2020 
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modafinil, a drug known to increase tonic LC activity and pupil 
diameter (Minzenberg, 2008), gabapentin, 1200 mg, or placebo.  Two 
hr later, pupil diameter increased after gabapentin and modafinil in 
comparison to placebo (Figure 6), consistent with an increase in LC 
activity from gabapentin in rodents (Hayashida, 2008) and in CSF NE 
in patients receiving gabapentin (Hayashida, 2007).  The proposed 
clinical study will test high-order interactions between pupil diameter, 
C↔O dimension and drug on speed of recovery from pain after TKA.  
If positive, this would explain the failure of gabapentin to exert large 
effects to reduce pain presence months after surgery in a general 
population and provide a testable algorithm to use simple patient 
characteristics – resting tonic LC activity as measured by pupillometry 
and C↔O style as measured by simple questionnaires – to those who 
may be most helped or most harmed by this drug.  An example of a tool using minimum effect sizes 
observable in the proposed clinical study is available at https://pain.shinyapps.io/clinicalPredictions/ 
(adjacent screenshot).  This tool assumes an inverted U effect of resting pupil diameter on speed of 
decline in noxious ascending input from the spinal cord and that of reliance on preferred style in the 
C↔O dimension.  The effect of gabapentin, which increases tonic LC activity, on speed of recovery will 
depend on both pre-drug pupil size and cognitive style in the C↔O dimension.  
 
 
In summary, the significance of the proposed work lies in 1) shifting dichotomous, static 
measures to continuous primary outcomes in recovery from surgery; 2) investigating several key, patient-
centered domains rather than just pain intensity in recovery; 3) providing a mechanistic hypothesis linking 
tonic LC activity and its interaction with C↔O style to speed of recovery across these domains; and 4) 
testing this hypothesis using a commonly applied therapeutic intervention to generate novel, clinically 
actionable results.   
 
 
Objectives 
 
We propose a two-site, longitudinal, randomized clinical intervention study to examine three 
specific aims: 
 
Aim 1: Characterize the dynamic pain experience, activity, and cognitive response after TKA or 
THA  and determine patterns of recovery in these domains 
 
Aim 2: Test whether gabapentin alters time course of recovery after TKA or THA in a manner 
dependent on its interaction with pre-drug pupil diameter and preferred style in the C↔O 
dimension  
 
 
Primary Hypothesis: Novel variance beyond established associations in recovery from pain following 
TKA or THA surgery is accounted for by the interaction between pupil diameter and C-A state, and this 
interaction predicts efficacy of gabapentin to speed recovery. 
 
Key secondary hypotheses: Disability, impulsivity, and attentional deficits recover after TKA or THA 
surgery follow a log of time pattern, and are predicted by C-A state and its interaction with pupil 
diameter. Gabapentin increases resting pupil diameter in patients scheduled for TKA or THA who are 
receiving high doses of opioids 
 
 
 

Protocol version: 3/5/2020 
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Methods and Measures 
 
Primary analysis: Three way Resting Pupil Diameter*C-A State*Drug treatment in the 250 subjects not 
on high dose opioids. 
 
Setting 
Subjects recruited at Wake Forest Baptist Medical Center will be identified by research personnel 
in the Departments of Anesthesiology and Orthopaedics. Research personnel will approach the 
subjects while they are in a private exam room, the study will be explained to the subject and the 
subject will be given a copy of the study consent form to read. Informed consent may be obtained 
at this time or the subject may choose to take the informed consent home and call the study 
personnel to schedule an appointment to come to the Headache and Pain Research Unit (HPRU) 
for consent and their initial study visit. Subjects will be seen in the HPRU (subjects may choose 
to have their 2 month and 6 month postoperative study visit occur in conjunction with their 
postoperative visit to their surgeon at Davie Medical Center) for 3 study visits; approximately 2 
weeks prior to surgery, approximately 8 weeks after surgery and 6 months after surgery. 
 
Subjects will also be recruited at the Cleveland Clinic in Cleveland, Ohio under the direction of 
Dr. Daniel Sessler, Professor and Chair, Cleveland Clinic Lerner College of Medicine. 
 
Subjects selection criteria 
We will recruit patients having primary, unilateral total knee arthroplasty (TKA) or unilateral 
total hip arthroplasty (THA). 
We will recruit  300 subjects in primary analysis - taking < 100 mg morphine equivalents/day 
(low dose opioid)  to test gabapentin’s effect on pupil diameter – taking >100 mg morphine 
equivalents/day (high dose opioid). 
 
• 
Inclusion Criteria 
Adult, non-pregnant adults scheduled for elective total knee replacement, American Society 
of Anesthesiologists physical status 1-3, able and willing to perform the study procedures. 
Individuals must be able to read and write English and have a stable residence. 
 
• 
Exclusion Criteria 
      (1) Inability to complete questionnaires; (2) Pregnancy; (3) Litigation or workers   
compensation related to their joint surgery;  (4) history of Raynaud’s disease of the feet; (5) 
suffering from a psychotic disorder or a recent psychiatric hospitalization; (6) history of eye 
surgery or topical eye medications that would render pupillometry unreliable or would directly 
affect pupil diameter; (7) any disorder that would affect pupil responsivity or prevent accuracy of 
pupillometry such as movement disorders. (8) Exclusion for preoperative calculated GFR <30 
ml/min, hold of study med if postop GFR<30 ml/min. (9) severe Chronic Obstructive Pulmonary 
Disease (COPD) requiring home oxygen. (10) Obstructive Sleep Apnea (OSA) with daily use of 
CPAP at home. 
 
• 
Sample Size 
Two-center interventional study of 300 evaluable patients having primary, unilateral TKA or 
unilateral THA at Wake Forest School of Medicine and Cleveland Clinic. Patients will be 
stratified by norepinephrine serotonin reuptake inhibitor (NSRI) use, 300 subjects not on high 
dose opioids will be included in the primary analysis to test the effect of gabapentin on 
resting pupil diameter. 
 

Protocol version: 3/5/2020 
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Interventions and Interactions 
Preoperative procedures. Eligible subjects will be identified at least 3 weeks prior to surgery, informed 
consent obtained, and a ~ 2hr preoperative assessment will be performed, consisting of 3 parts. We will 
record demographic and history information, including pre-existing pain elsewhere, female subjects of 
child-bearing potential will have a urine pregnancy test performed. 
In the first part we will administer thermal heat temperatures ranging from warm but not 
painful to painfully hot. We will ask subjects to indicate when they feel warmth or pain, and to 
rate the pain using a scale from 0-10.  
The second part will consist of subjects to completing a series of 3 questionnaires on the 
computer, 2 questionnaires on paper, and play 2 simple card games.  
The third part will consist of the subject experiencing the warm and hot temperatures again 
while we make a recording of their pupils.  
We will administer questionnaire-based measures of psychological state, physical function, and pain 
(Table 1). Questionnaire responses will be entered via a custom designed REDCap data entry form and 
checked for completeness by the data coordinating center. We will have the subjects complete 2 of the 
questionnaires (PLOC and PSE) on paper the evening before the visit as well as the PAS and DSI. 
The LOT-R, PCS, and WOMAC will be completed on the computer   during the first visit. The remaining 
questionnaires will be completed at home and returned to the study team on the day of surgery (Stanford 
Expectations of Therapy Scale, PROMIS-Depression, PROMIS-Anxiety, PMAQ, Barratt Impulsivity, 
Fear of Pain, TSK, WHODAS 2.0, BRS)From these questionnaires, we will place each participant on a  
dimensional continuum that describes their 
general cognitive style. We will use 
multidimensional scaling (MDS) to force 
catastrophizing and optimism as 2 ends of 
this continuum (Figure 7). These 
questionnaires will assess activities of daily 
living and associated disabilities. 
Upon review of the questionnaire data, the 
study staff will notify the primary attending 
surgeon for any subject showing suicidal 
ideation as well as the study staff will call 
the subject and inform them. 
 
The Daily Stress Inventory (DSI) 
and the Perceived Arousal Scale (PAS) will 
be completed the night before the scheduled 
appointment and the PAS will be completed 
once during the scheduled appointment. The 
Modified Pain DETECT will also be 
completed during visit 1.  
 
These two constructs describe cognitive styles that are strongly inversely associated with each 
other; MDS will provide the optimal weights to best order individuals on this latent scale. Studies have 
examined the interplay of these constructs with other psychological concepts such as acceptance, pain-
related disability and psychosocial adjustment and have found that both are reliably associated with the 
positive and negative aspects of the adjustment to pain.                                             
 
 
 
 
Table 1.  Preoperative Questionnaire 
Stanford Expectations of Therapy Scale 
WOMAC- Osteoarthritis Index 
Life Orientation Test-Revised (LOT-R) 
PROMIS- Depression 
PROMIS- Anxiety 
Pain Medication Attitudes Questionnaire (PMAQ) 
Pain Locus of Control Scale (PLOC) 
Pain Self-Efficacy Scale (PSE) 
Barratt Impulsivity Test 
Fear of Pain Questionnaire 
Pain Catastrophizing Scale (PCS) 
Tampa Scale of Kinesiophobia (TSK) 
WHO Disability Assessment (WHODAS 2.0) 
Brief Resiliency Scale (BRS)  
Modified Pain DETECT 
Daily Stress Inventory (DSI) 
Perceived Arousal Scale (PAS) 

Protocol version: 3/5/2020 
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We will perform pupillometry during presentation of calibrated noxious stimuli. Subjects will 
report pain and unpleasantness using mechanical 10 cm visual analog scales (VAS) to 5 sec duration heat 
stimuli (37⁰ to 50⁰ C in 2⁰ increments) applied to a 2 cm2 area of skin on the forearm using Peltier-
controlled thermode (TSA-II®, 
Medoc, Ramat Yishai, Israel). 
Stimuli will be separated by 30 
sec and the all temperatures 
will be presented in an 
ascending series for training 
followed by a random series to 
generate a stimulus response as 
previously described (Hood, 
1995; Eisenach, 2010). We will 
deliver 3 blocks of thermal 
stimuli to each subject for the 
pupillometry session. The blocks will include the same temperatures (37⁰C; warm threshold, 46⁰C; pain 
threshold and 50⁰C; painful stimuli) delivered 3 times each per block. Each block will consist of a 
random presentation of these temperatures. We will provide verbal instructions to the subjects 
immediately prior to the block: block 1 will be labeled as ½ of the stimuli will be painful and ½ of the 
stimuli will not be painful, block 2 will be labeled as 80% of the stimuli will be painful and block 3 will 
be labeled as 20% of the stimuli will be painful.   The thermal probe will be moved to a different area of 
skin on the forearm for each testing sequence. The debriefing statement is included in Appendix 3. 
We will then test CPM as previously described (Nahman-Averbuch, 2013) by recording VAS 
pain and unpleasantness from a 5 sec, 49⁰C stimulus on the volar forearm before, 30 sec after insertion of 
the foot of the extremity not planned for operation in 10⁰C water, the foot will remain in the water for a 
total of 90 seconds.   During pain testing, study subjects will sit in a comfortable chair in a low-ambient 
light room with their head positioned on a chinrest for continuous recording of pupil diameter using a 
near infrared recording system as described in preliminary data. Pupil diameter and probe temperature 
will be passed through an analog to digital and acquired at 60Hz for subsequent analysis.  
We will have the subjects wear a portable heart monitor during the study visit so that the 
researchers can record the heart rate to assess the state of arousal to coincide with the PAS questionnaire 
that will be completed. The heart rate monitor will be a non-invasive monitor. 
 
Subjects will be trained and provided with a tablet device for daily diary entries and the 
accelerometer. The accelerometer has wireless connectivity such that daily diary and activity will be time 
stamped and can be easily uploaded by the patient to the data coordinating center on a regular basis. We 
will utilize a password protected web based database tool for near real-time access to facilitate adherence 
(e.g., phone calls or emails when participants fail to wear the device during regularly scheduled time 
points). 
 
We will have subjects begin using the tablet and wearing the accelerometer 2 weeks prior to 
surgery so that they will become familiar with the devices to increase compliance and adherence to the 
protocol after surgery. 
 
 
The tablet will also have the capabilities to access PEBL software for cognitive assessment. This 
open-source software employs several cognitive tasks that look and feel like challenging games that allow 
the assessment of different areas of cognitive function. The specific tasks will be the Iowa Gambling Task 
to assess impulsivity. The Wisconsin Card Sorting Task will be utilized to assess executive function. 
Participants will complete these tasks at baseline and again at several times after hospital discharge 
(Figure 8). 
 
Figure 7: The dimensional structure of the 
continuum of cognitive style to be used, 
including psychosocial constructs associated 
with each end 

Protocol version: 3/5/2020 
9 
 
 
 
Drug treatment. Patients will be randomized, stratifying for NSRI use, to equal number to receive 
gabapentin of placebo pills formulated by the research pharmacy at the institutions. Drug treatment will 
begin 2 weeks prior to surgery and continue 3 weeks afterwards. To reduce treatment-limiting side effects 
subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 
weeks, and 900 mg/day for the last week (Figure 8). Subjects will be contacted 5 days after beginning the 
1800 mg dose and assessed for bothersome side effects (sleepiness, dizziness, confusion) that are 
interfering with normal activities of daily living(ADL’s). If bothersome side effects are present at this 
time dose will be decreased back to 900mg/day. Subjects’ will receive a weekly phone call while on study 
drug treatment and assessed for side effects, difficulty breathing or falls that have occurred.  
 
Intraoperative and in-hospital care. We will not limit intraoperative surgical or anesthetic management 
or in-hospital analgesic management. A study team member will record potential confounds including 
surgical complications, in-hospital physical therapy, intraoperative and postoperative opioid, gabapentin, 
ketamine, and regional anesthesia administration, and days from surgery to discharge. For patients 
receiving a spinal injection as part of clinical care, we will collect a 2 ml CSF sample for planned 
exploratory analyses for measures of noradrenergic activity (norepinephrine) and chronic stress state 
(NPY, cortisol, IL-1β). Research staff will see the subject daily in the hospital to have them complete the 
daily diary questions. Study medication will be held during hospitalization if postoperatively the 
calculated GFR<30 ml/min until resolution of lab abnormality. 
 
Post-hospital discharge measures. Patients will begin daily evening electronic diary entries on the day of 
hospital discharge for 8 weeks then once monthly (beginning 3 months after surgery) study staff will call 
the subject to collect the diary questions until 6 months after surgery. Patients will also answer a weekly 
WHODAS 2.0 (12 questions) on the electronic diary and will complete this monthly during their phone 
call as well.  These assessments will typically take less than 2 minutes and assess IMMPACT 
recommended domains (Turk, 2006): pain intensity, physical functioning, emotional functioning, and 
participant ratings of global improvement and associated symptoms. Electronic diary entries are captured 
wirelessly using the participant’s home wireless connection via the customized secure electronic, 
password protected database. Both sites will be provided with several tablets that are equipped with pre-
paid 4G wireless access to ensure that participants without home Internet connections can participate. The 
diaries will be monitored and maintained by the data coordinating center in real-time; if a participant 
misses a diary entry, they will be emailed or called (their preference) to ensure maximal adherence to the 
protocol. Using these procedures we have been able to obtain > 95% adherence in our previous diary 
studies. Participants will also wear the accelerometer for the first 8 weeks after discharge. Participants 
will also complete the cognitive tasks (Iowa Gambling Task, Wisconsin Card Sort,) that they were 
introduced to at the baseline session at, 2 months, and 6 months after hospital discharge. The Iowa 
Gambling Task will again be administered via the PEBL software. Questionnaires done at pre-
randomization (Table 2) will be repeated at 2 and 6 months after surgery. Finally, we will also record 
objective assessments of joint function at the times when the subjects return to clinic for their 
postoperative visits. 
 
Figure 8: 
Timeline of 
study.  
Cognitive tasks 
are performed at 
circled times. 

Protocol version: 3/5/2020 
10 
Subject payment: Subjects will be paid $1000 with pro-rated payment steps (listed below) to study 
completion. An additional incentive will be provided in the form of the Fitbit at the end of the subject’s 
use in the study. The tablet devices will be returned to each study center for re-use. 
Pro-rated payment will be made as follows:  
 
• 
$300 for completion of the  preoperative HPRU study visit, 
• 
$50 for completion of questionnaires 2 months after surgery (HPRU or Davie Medical Center) 
• 
$50 for completion of questionnaires 6 months after surgery and return of study supplies 
(electronic tablet, charge, wireless internet card) completed in the HPRU or Davie Medical 
Center 
• 
$200 for completing at least 90% of the daily diary entries on the electronic tablet and wearing 
the accelerometer weeks 1 through 8 at least 90% of required time 
• 
$400 for completion of all the scheduled study visits and postoperative assessment/questionnaires 
(At the end of the 6 month assessment: the electronic diary must be returned (including the 
charger) and the wireless card for compensation to be processed) 
 
 
If a subject withdraws for any reason from the study before completion they will be paid according to the 
schedule of payment above.  The accelerometer and the tablet must be returned if a subject withdraws 
from the study prior to completion for payment to be processed for the portion of the study completed. 
 
To encourage good effort on the Iowa Gambling Task (IGT), a yearly raffle (after 40 completed subjects) 
of $500 will be held.  All subjects who complete the IGT will have one raffle ticket entered into the 
drawing, regardless of net earnings.  In addition, each $100 of net earnings will earn the participant an 
additional raffle ticket.   For example, if a subject completes the IGT and has net earnings of $300, he/she 
will have four tickets entered in the raffle.  Prior research suggests that providing monetary reinforcement 
on the IGT improves overall performance and reduces performance variability. (Fernie G, Tunney RJ. 
Some decks are better than others: The effect of reinforcer type and task instructions on learning in the 
Iowa Gambling Task. Brain and Cognition. 2006;60:94–102.)  
 
 
Analytical Plan 
Data analysis. The plan of analysis and sample size estimation for the primary analysis is presented in 
full detail in the Bioinformatics Core (Appendix). Briefly, we will examine the frequently obtained (i.e., 
daily, then monthly) worst daily pain intensity score and the total daily (i.e., non-sleep) accelerometer 
movement score. One growth curve model will be created for each outcome (pain, movement) using all of 
the predictors in Table 2, strength of conditioned pain modulation (CPM) from the laboratory session. 
Additionally, one model that combines both outcomes will examine for lagged and synchronous 
relationships between the two outcomes (i.e., do changes in one outcome predate changes in the other?). 
See the Bioinformatics Core for details about the handling of nuisance variables (e.g., site effects, 
surgeon), missing data, and sensitivity analyses. Pupil diameter data will be conditioned to remove blink 
and saccade artifacts and smoothed using an autoregressive filter. The local resting diameter will be 
determined representing the average smoothed value for the 500 msec preceding the stimulus onset. The 
pupil response to each stimulus is calculated as the mean pupil diameter during the 5 sec stimulus after 
accounting for lag time from onset of stimulus to onset of pupil response and is expressed as a % change 
from the local resting diameter (see our preliminary data for examples). Multidimensional Scaling (MDS) 
will be used to create a single dimensional scale from the catastrophizing and optimism scores (i.e., 
responses from these two questionnaires will be weighted and scaled to create a single-dimensional 
construct) to determine the interaction among the factors of interest, and to accommodate the many 
repeated measures within each participant, we will utilize Generalized Estimating Equations. In our 

Protocol version: 3/5/2020 
11 
experience, the pupil response to painful stimuli is well modeled by a normal distribution with an identity 
link and an AR1 repeated measures covariance structure. To examine our hypotheses, we will model 
percent pupil change (the DV) using fixed effects for stimulus temperature, catastrophizing-optimism 
score (i.e., C-A state), and pre-stimulus baseline pupil diameter (i.e., LC activity). The association 
between C-A state and pain reporting will first be examined, and in a later block the moderating effect of 
baseline pupil size will be entered. Statistically significant interaction between baseline pupil diameter 
and the relationship between C-A state and pain reporting will be interpreted as support for the primary 
hypothesis (1). Primary hypothesis (2) will be tested by comparing placebo to gabapentin resting pupil 
diameter after controlling for condition and stimulus intensity. Secondary analyses will include the effect 
of drug and C-A state on condition. Please see the Bioinformatics Core for more details as well as for 
statistical power considerations. 
We assume that the mechanisms underlying this association are the same in total knee 
arthroplasty and total hip arthroplasty patients, but that the two groups will have different 
intercepts (pain at discharge) and slopes (recovery times after surgery). These surgical 
differences will be modeled using an additional fixed effect for intercept and slope in our 
primary model. We do not expect these additional fixed effects to be correlated with the 
predictors used in the primary hypothesis, so the original statistical power calculation is 
unchanged. We will modify the statistical analysis plan to reflect these changes in the expected 
statistical model.     
 
Outcome Measure(s) 
Primary outcome measure: Modeled trajectory of recovery from pain using a log of time form. 
 
Several secondary analyses are planned that examine changes in cognition (e.g., impulsivity, attention) as 
well as kinesiophobia. The cognition measures (Iowa Gambling Task, Wisconsin Card Sort, TSK) 
collected at baseline, , 2 months and 6 months after discharge will be examined using generalized linear 
model with Time (BL, , 2mo, 6mo) as a fixed factor. Please see the Bioinformatics Core for complete 
details. Finally, we will collect and secondarily examine biomarkers for stress and noradrenergic 
functioning by exploring the relationship between preoperative patient characteristics, including 
psychophysical responses to pain processing and CSF concentrations of norepinephrine and markers 
associated with stress. 
 
Human Subjects Protection 
Subject Recruitment Methods 
Appropriate subjects will be identified and approached in the Department of Orthopedics during their 
regular scheduled appointment, by research personnel. Research personnel will utilize a private exam 
room to talk with subjects. Subjects will be given the study details and the opportunity to read the 
informed consent. The subject may take the informed consent home and make their decision regarding 
study participation.  Contact information for the research staff will be provided to the subject so that they 
may call for questions or to participate.  Study personnel will make every effort to approach any subject 
that will be scheduled for primary TKA or THA.  
 
Informed Consent 
Signed informed consent will be obtained from each subject. Research personnel will obtain informed 
consent, the subject may sign the informed consent during their appointment time in the Orthopedic 
Clinic or the informed consent may be reviewed and signed during their first scheduled visit to the 
Headache and Pain Research Unit (HPRU). If the subject has signed the informed consent prior to their 
first HPRU visit, consent will be confirmed and all questions answered prior to any study procedures.  No 
study information or procedures will be performed prior to the subject signing the informed consent. 
All subjects will be given a copy of the signed, informed consent.   

Protocol version: 3/5/2020 
12 
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.  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. 
 
 
Risks.  
 
The thermal heat testing may be discomforting (however, subjects are not exposed to 
temperatures greater than they would experience in everyday life.) The heat probe can cause a temporary 
redness of the skin for several hours.  The risk of burn is very remote.  We will remove the probe any 
time the subject requests. The subject may also move their extremity away from the thermal heat probe at 
any time. The device is a computer controlled, water cooled device that has safety mechanisms in place to 
prevent extreme temperatures from being utilized. Additionally, we have used this device for > 10 years 
and have not had any reported burns.  
 
 Pulmonary 
                Gabapentin has been associated with serious breathing difficulties in patients taking opioids and 
those with diseases that reduce lung function including chronic obstructive pulmonary disease (COPD).  
Symptoms include confusion, unusual dizziness or lightheadedness, extreme sleepiness, slowed, shallow 
or difficult breathing, unresponsiveness, and bluish colored or tinted skin, especially on the lips, fingers, 
or toes. 
 
The most common side effects (greater than 2%) of gabapentin are listed in the table below: 
 
Body System/Preferred Term  
  
 
 
Neurontin
®   
Placebo  
 
 
 
 
 
 
 
 
N=336  
N=227 % %  
Body as a Whole  
Asthenia  
 
 
 
 
 
 
5.7  
 
4.8  
Infection  
 
 
 
 
 
 
5.1  
 
3.5  
Headache  
 
 
 
 
 
 
3.3  
 
3.1  
Accidental injury  
 
 
 
 
 
3.3  
 
1.3  
Abdominal pain  
 
 
 
 
 
2.7  
 
2.6  
 
Digestive System  
Diarrhea  
 
 
 
 
 
 
5.7  
 
3.1  
Dry mouth  
 
 
 
 
 
 
4.8  
 
1.3  
Constipation   
 
 
 
 
 
3.9  
 
1.8  
Nausea  
 
 
 
 
 
 
3.9  
 
3.1  
Vomiting  
 
 
 
 
 
 
3.3  
 
1.8  
Flatulence  
 
 
 
 
 
 
2.1  
 
1.8  
 
 

Protocol version: 3/5/2020 
13 
Metabolic and Nutritional Disorders  
Peripheral edema  
 
 
 
 
 
8.3  
 
2.2  
 
Nervous System  
Dizziness  
 
 
 
 
 
 
28.0  
 
7.5  
Somnolence  
 
 
 
 
 
 
21.4  
 
5.3  
Ataxia   
 
 
 
 
 
 
3.3  
 
0.0  
Thinking abnormal  
 
 
 
 
 
2.7  
 
0.0  
 
Special Senses  
Amblyopia
a  
 
 
 
 
 
 
2.7  
 
0.9  
 
a Reported as blurred vision  
Other events in more than 1% of patients but equally or more frequent in the placebo group included 
pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.  
 
The incidence of depression and confusion were reported as frequent (defined as occurring in at 
least 1/100 patients).   
 
 
Safe chronic ocular exposure values to Infrared, Range A (IR-A), are in the range of 10mW/cm2 
or below.   The largest eye irradiance noted with the near infrared recording system that will be utilized for 
this protocol is between 0.75 - 0.80 mW/cm2 at the plane of the eye. Under normal use, eye irradiance is 
between 0.1 – 0.3 mW/cm2. 
 
 
Protections Against Risk From Providing Data. 
• 
Data security: Electronic data will be maintained in a password protected database, on password 
protected servers, to which only the study team has access. Daily hand-held data is de-identified, 
and is transferred to lab computers via a secure connection. REDCap is a HIPAA compliant, 
secure database system. Data validity will be maintained by validity criterion in the database, and 
errorchecking procedures. Study staff will complete training in HIPAA regulations, and will be 
clearly instructed not to divulge confidential information regarding subjects. The system will also 
be developed in accordance with FDA Part 11 [21CFR11] guidelines. Participant records are kept 
confidential, with paper records in a secure location and computer records password protected, 
available only to study staff. 
• 
CSF will be obtained by a board certified anesthesiologist during the course of routine care in 
providing spinal anesthesia. 
• 
Symptoms of depression, anxiety, and other forms of psychological distress symptoms are to be 
measured upon enrollment. Because many patients will endorse some level of distress, and it is 
impossible to know for each individual when they require or are even open to mental health 
assistance. Therefore, and because our questions may focus patients attention on these sources of 
significant distress, we will offer a referral to a mental health professional to ALL patients. To be 
specific, we will provide all patients with telephone numbers and addresses of at least three local 
mental health resources. We will not explicitly seek suicidal ideation. Patients spontaneously 
endorsing thoughts of harming themselves or others will have their treating physician informed 
for an assessment if they need to be guided to the emergency room, or other care pathway. 
 
 

Protocol version: 3/5/2020 
14 
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. 
 
The DSMP outlined below will provide appropriate oversight and monitoring to ensure the safety of 
participants, the validity of the data, and make intermittent recommendations whether to continue, modify 
or stop the study. The DSMP will utilize an independent DSMB to ensure the effective institution of the 
DSMP. 
 
This DSMB will have discretion to unblind any results, or conduct any inquiry needed to ensure the 
safety and efficacy of the trial at the request of the DSMB chair. The committee will maintain a written 
record of its meetings. 
 
Scope of Data Monitoring 
The primary source of the data will be the entered questionnaire data and adverse event reporting. 
 
Study admission data 
Monitoring of admission data will include the number of subjects requesting participation in the study, 
number of subjects screened and number of subjects admitted to the study. The DSMB may request a 
report of the reason why subjects were disqualified from participating in the study. For subjects admitted 
to the study, the DSMB will review eligibility criteria for admitted subject, any protocol deviations and/or 
violations, and the demographic distribution of the subjects by group. 
 
Protocol Compliance 
The DSMB will monitor the data to assess compliance with the protocol including the adherence to the 
randomization schedule. The DSMB will also monitor the quality and completeness of the data being 
collected, including the frequency of missing or erroneous data, and presence and frequency of outliers. 
 
Safety Data 
Monitoring of safety data will include review of Adverse Events (AEs) and Serious Adverse Events 
(SAEs), trial retention, and reason for drop out. Safety information will be reported to the DSMB in an 
unblinded manner. Formal statistical analyses of the safety data may be requested by the DSMB. For 
SAEs, data will include all the adverse event data meeting the FDA definition of serious adverse events. 
In the assessment of SAEs, the DSMB will review each individual case including treatment group 
assignment. After each meeting of the DSMB, the secretary will forward a summary report of all serious 
and unexpected adverse experiences to the principal investigator to summarize the DSMB's review of the 
serious and unexpected adverse events reported. Furthermore, the DSMB will make a recommendation to 
continue, modify or halt the study protocol. This report will be transmitted to the Wake Forest University 
IRB and NIH. Safety data will be prepared for review following the enrollment of each 40 subjects. 
 
Establishing a DSMB Board membership 
The DSMB will be appointed by Dr. Eisenach and Dr. Houle with the purpose of reviewing, approval, 
and monitoring the implementation of the DSMP. The DSMB will have three members encompassing 
multidisciplinary expertise who are not involved in the study protocol. Board members will have no 
financial and/or scientific ties to the outcome of the clinical trial to avoid any real or perceived conflict of 
interest. At the start of each new member's term, the individual will sign a confidentiality statement 
promising not to disclose any proprietary and nonproprietary data. The DSMB will include the following 
physicians; Peter Pan, M.D., Professor of Anesthesiology, Robert Weller, M.D., Professor of 
Anesthesiology and Dennis Ang, M.D., Associate Professor of Rheumatology and Immunology. 
 
 

Protocol version: 3/5/2020 
15 
Board meeting schedule 
The board will have scheduled meetings twice a year and expedited meetings to review unexpected SAEs 
or other urgent issues that may arise during the trial. Unscheduled meetings may be initiated by the 
DSMB chair, Dr. Eisenach, or Dr. Houle. The data to be reviewed by the DSMB will be available to the 
Board members. 
 
DSMB Recommendations: 
DSMB recommendations will be made in writing by The DSMB chair to Dr. Eisenach. The secretary will 
prepare meeting minutes for inclusion in the DSMB report. The draft report will be reviewed by all Board 
members prior to issuance of the final report. DSMB recommendations will then be forwarded to the 
NIGMS program officer and Wake Forest University IRB. 
 
 
 
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. 
 
 
Appendix 
1. Bioinformatics Core 
2. Copies of each questionnaires or surveys that will be used 
3. Debriefing statement 
 
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