A Feasibility Study: Understanding and Altering Pain Expectations in Subjects With Osteoarthritis of the Knee or Hip
Phase: PHASE4
Conditions: Osteoarthritis
Sponsor: Wake Forest University Health Sciences

11/06/2014 
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A Feasibility Study: Understanding and Altering Pain Expectations in Subjects with 
Osteoarthritis of the Knee or Hip 
 
11/6/2014 
 
NCT02155257  
 

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Why a feasibility study 
 
 
 
In May we submitted a Program Project Grant (P01) application to the NIH.  This $10 
million effort would fund a group of laboratory and clinical investigations to better understand 
and prevent the problem of chronic pain and disability after major surgery.  Although we 
provided some preliminary data with that application, we expect that additional feasibility data 
will be required for the application to reach a level of priority high enough for funding.  The 
current IRB application is to collect those feasibility data in time for a November, 2014 revision. 
 
 
Both chronic pain and disability after total knee replacement surgery are predicted by 
negative cognitive-affective state, characterized by depression, anxiety, and a cognitive style 
dominated by catastrophizing.  How this negative state results in chronic pain and disability is 
not known, but we hypothesize that it causes dysfunction of the release of the neurotransmitter, 
norepinephrine in several regions of the brain, mid-brain, and spinal cord that are important to 
many processes involved in recovery from surgery.  In the P01 grant application we propose to 
test these circuits in animals and to study patients after total knee replacement as well as those 
with moderate daily pain and osteoarthritis who are not undergoing surgery.  This protocol is to 
generate feasibility data for the osteoarthritis study in time for the Nov, 2014 revision, if it is 
needed. 
 
Background 
 
 
The locus coeruleus (LC) as a regulator of gain.  The LC is a small collection of 
neurons in the pons which provides the exclusive or near-exclusive noradrenergic innervation to 
the cortex, spinal cord, and mid-brain.  Although involved in many 
processes, the diffuse cortical projections from the LC are key 
regulators of gain of overall brain network function and response 
(Eldar, 2013).  As opposed to amplification, which results in 
increased signals from all components of a complex circuit, 
increasing gain results in increased dominance of strong signals at 
the expense of weak signals (Figure 1).  In humans, increased LC 
activity and inferred gain sharpens connectivity as determined by 
fMRI such that weak connections become weaker and strong 
connections become stronger (Eldar, 2013).  That study compared 
learning with abstract versus visual tests, and showed that 
increased gain resulted in stronger reliance on the individual’s 
preferred learning style.  In other words, when gain was low, 
individuals learned by either style, visual or abstract, but when gain 
was high, they relied much more heavily on their preferred style.  
Those who rated themselves better as visual learners became even 
better at the visual learning tasks and worse at the abstract learning tasks under high gain 
conditions, whereas the abstract learners did the opposite.  Thus, gain determines how much 
one applies their preferred mode of response to a stimulus, situation, or task. 
 
 
Pain is a recurrent, powerful stimulus after surgery or in those with advanced arthritis, 
and the gain concept suggests that experience of intermittent pain reflects not just how the 
underlying personality factor interacts with the stimulus itself, but also how high the gain is.  
Data from an ongoing preliminary study in the CRU at Wake Forest in healthy volunteers 
receiving experimental pain stimuli support this idea.   
 
Figure 1: Gain sharpens 
output by altering input 
strength (Eldar, 2013) 

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The pupil reports LC activity and gain.  Studies in animals with electrodes implanted 
in the LC and in humans with fMRI imaging of the LC suggest that changes in pupil diameter 
faithfully report LC activity (Gilzenrat, 2010; Payzan-Lenestour, 2013; Eldar, 2013).  Our 
ongoing study in healthy volunteers asked how pupil responses could predict experience of pain 
from experimental stimuli. 
 
 
In this ongoing study we have examined pupil 
responses to phasic noxious heat stimuli to date in 19 
normal volunteers and 4 subjects with migraine (but not 
in the presence of a headache).  Studies were 
performed in a room with constant, low ambient light so 
that both constriction and dilation of the pupil could be 
observed.  Pupil diameter was continuous monitored by 
an infrared camera (Eye-Trac™  system; Applied 
Science Laboratories) with the subject’s chin resting on 
a chin rest and gaze on a fixed object presented on a 
monitor.  A 4 cm2 Peltier-controlled thermode was 
placed on the calf, with temperature maintained at 
35⁰C and 5 sec stimuli at various temperatures applied 
every 30 sec.  Subjects reported pain intensity with a visual analog scale (VAS) fro 0 (no pain) 
to 100 (worst pain imaginable).  Increasing probe temperature to 50⁰C resulted in pain report 
and pupil dilation, the former with a longer lag (Figure 2, typical response).  As previously 
described with other stimuli (Chapman, 1999; Oka, 2007), there was a direct relationship 
between pupil dilation and noxious heat temperature as well as VAS pain intensity and 
unpleasantness. 
 
 
 
We next examined the relationship between 
pupil response and pain report as a function of 
affective distress. We estimated affective distress as 
the sum of scores to the pain catastrophizing scale, 
the CSED depression scale, the state trait anxiety 
inventory, and the pain anxiety symptom scale and 
linearly regressed this on pain report.  The residual 
from the regression line for each individual was 
related to baseline pupil diameter as a measure of 
tonic LC activity.  Despite there being a very small 
range of affective distress in this largely normal 
population, the residual (tendency to adhere to 
cognitive-affective state in pain reporting) was 
significantly related to baseline pupil diameter (Figure 
3).   
 
 
Expectations alter pain experience.  We are also manipulating expectations in this 
study of healthy volunteers. Pain stimuli are first presented as a random series without cues, 
then as a series preceded by 6 sec with an auditory cue to indicate whether the stimulus would 
be mildly (47⁰C) or moderately (50⁰C) painful, then as a series with 20% of the cues incorrect.  
So far we have observed a mild, but highly significant reduction in pain from random to cued 
condition, consistent with a recent report on the role of uncertainty in pain reporting (Yoshida, 
2013).  During miscuing, there was a greater effect of negative expectations (expect less pain) 
than positive ones (expect more pain), as previously reported (Koyama, 2005).  In the proposed 
Figure 3: Relationship between resting 
               pupil diameter and pain  
               reporting by affective distress 
Figure 2: Time course of heat stimulus 
           and of VAS and pupil responses 

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study we gather feasibility data in a clinical population (patients with moderate osteoarthritis of 
the hip or knee) to test whether we can manipulate expectations on pain in this population.  
 
 
Gabapentin and modafinil to increase LC activity and gain.  In animals and humans, 
the alertness enhancing drug, modafinil (Provigil™) increases tonic LC activity and increases  
pupil diameter.  Although large doses of this drug (800 mg) can increase blood pressure and 
heart rate, this has not been observed in these studies of over 100 people who received 200 mg 
(Hou, 2005; Nikolaou, 2008; Minzenberg, 2008; Schmaal, 2013; Geng, 2013).  For this reason, 
we will examine the effects of modafinil, 200 mg, on pupil diameter and its effect to alter pain 
reporting as a function of baseline state by increasing gain. 
 
 
A more relevant drug to the question of chronic pain after surgery is gabapentin, and 
some clinical trials have suggested that perioperative treatment of this drug can reduce the 
incidence of this problem (Schmidt, 2013).  In the NIH application we propose to test gabapentin 
rather than modafinil because our previous work with direct measures in rats and cerebrospinal 
fluid norepinephrine sampling in humans is consistent with gabapentin activating LC in both 
species (Hayashida, 2007).  The pupil measurements in this feasibility study will more directly 
assess whether gabapentin does indeed increase LC activity in humans.  Should it fail to 
demonstrate a reasonable effect size to dilate the pupil, we will revise the NIH application to 
study modafinil rather than gabapentin.  As such, these preliminary data are very important to 
the design of the final study. 
   
 
Study Design.  
 
Hypotheses: (1) Gabapentin and modafinil will increase resting pupil diameter with a 
moderate effect size in patients with osteoarthritis; (2) Expectations will modify pain experience 
with a moderate effect size in these patients  
 
 
Study design:  Single-center, randomized, controlled study of gabapentin, modafinil, 
and placebo in 30 subjects (10 per group) with moderate osteoarthritis pain of the hip or knee or 
healthy individuals without pain 
 
 
Primary outcome measures:  (1) Resting pupil diameter and response to noxious 
stimuli after study drug; (2) Interaction between resting pupil diameter and correlation of 
cognitive-affective state to pain reporting.  
 
 
Inclusion criteria:  Adult, nonpregnant adults scheduled with moderate pain (verbal 
score of ≥ 4 ≤ 7 on 0-10 scale for average pain intensity with normal activity) from osteoarthritis 
of the knee or hip, or healthy individuals without pain, American Society of Anesthesiologists 
physical status 1-3, able and willing to perform the study procedures, including sitting in a chair 
for 45 min.  Individuals must be able to read.  
 
 
Exclusion criteria. (1) Inability to complete questionnaires; (2) Pregnancy; (3) Currently 
taking gabapentin or > 50 mg morphine equivalents/day; (4) advanced or unstable cardiac, 
pulmonary, renal or hepatic dysfunction; (5) history of previous eye surgery; (6) psychotic 
disorder or a recent psychiatric hospitalization. 
 
 
Catastrophizing-Optimism continuum assessment.  Prior to the initiation of 
experimental procedures, each participant will be administered the battery of questionnaires 
Table 1. 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 4). These two constructs 

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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.  
 
 
Study procedures:  A total of 
30 subjects with moderate average 
daily pain from osteoarthritis of the 
knee or hip or subjects with no pain will be recruited and will come to the clinical research unit at 
Wake Forest.  Informed 
consent will be confirmed 
and they will complete the 
questionnaires. We will take 
a verbal medical and 
medication history and 
obtain blood pressure and 
heart rate measurements. 
Verbal pain intensity report 
(0-10 from no pain to worst 
pain imaginable) will be 
obtained from 5 sec heat 
stimuli, separated by 30 
sec, delivered to a 
nonpainful area of skin on 
the arm as described in preliminary data.  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 converter and acquired at 60 Hz for subsequent analysis. 
 
 
Five sequences of test stimuli will be presented, with a brief break in between each 
sequence (Figure 5A).  The first sequence will consist of 7 stimuli, from 39⁰ to 51⁰ C in 2⁰C 
increments, in ascending order.  Data from this training sequence will not be used for analysis.  
Sequences 2 and 3 will consist of 5, 5-sec stimuli, presented in random order, to generate 
moderate (50⁰C) and mild (47⁰C) pain (random condition).  Sequences 4 and 5 will also consist 
of random presentation of 5 stimuli at these temperatures, but with different auditory tones 6 s 
prior to stimulus onset to correctly cue the stimulus temperature (cued condition).   
 
 
Subjects will then be randomized to receive oral gabapentin, 900 mg, modafinil, 200 mg, 
or placebo, followed 2 hr later by pain testing with pupillometry, consisting of different 
sequences (Figure 5B).  The random and cued paradigms will be presented twice each (only 1 
representative shown in Figure 5B), followed by a sequence with one miscue in the positive 
expectation for pain direction (signal for 50⁰C but deliver 47⁰C) and one in the negative 
Table 1.  Questionnaires 
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) 
Figure 4: The dimensional structure of the continuum of cognitive 
style to be used, including psychosocial constructs associated with 
each end. 

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expectation for pain direction (mistrust condition, yellow bars in Figure 5B).  Subjects will 
provide verbal pain intensity scores after each stimulus.    
The pre-drug and post-drug set of sequences will take approximately 30-40 min including 
breaks between sequences of stimuli.  Following this subjects will be discharged from the  
clinical research unit accompanied by a responsible adult.  
 
 
 
 
Subject payment.  Subjects will be paid $250 for participation in the study. 
 
 
Data analysis.  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 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., cognitive-affective state), and pre-stimulus 
baseline pupil diameter (i.e., LC activity). The association between cognitive-affective state and 
pain reporting will first be examined, and in a later block the moderating effect of baseline pupil 
size will be entered.  
 
Figure 5: Heat stimuli give before (A) or after (B) study drug 

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The goal of this feasibility study is to estimate the effect size of drugs on pupil diameter and 
the strength of interaction between pupil diameter and the relationship between cognitive-
affective state.   
 
 
Expected results.  We anticipate, based on preliminary data, that pain reporting will be 
weakly correlated with cognitive-affective state and that resting pupil diameter as a reporter of 
LC gain will interact with this correlation or tendency to apply cognitive style to pain reporting.  
We anticipate overall reduced pain reporting after placebo (placebo effect)  and that the 
magnitude of this reduction and that of negative of pain will be inversely related to location on 
the optimism-catastrophizing continuum (i.e., greater placebo effect, greater effect of negative 
expectations of pain, and lesser effect of positive expectations of pain in strong optimists).  After 
gabapentin or modafinil we anticipate that resting pupil diameter will be greater (i.e. greater 
tonic LC activity) than placebo.  According to the gain concept, the effect of gabapentin on pain 
reporting across conditions should depend on cognitive-affective state, with overall reductions in 
pain reporting in strong optimists and amplification of pain in strong catastrophizers.  The study 
is not powered to definitively show the effects of these drugs on either pupil diameter or its 
relationship to pain reporting as a function of optimism-catastrophizing.  Rather, it is to provide 
feasibility, effect size, and variability data to support the choice of drug and power analysis for 
the eventual controlled study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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