Biopsychosocial Influence on Shoulder Pain: a Randomized, Pre-clinical Trial
Phase: PHASE2
Conditions: Shoulder Pain
Sponsor: Duke University

Biopsychosocial Influence on Shoulder Pain (BISP) 
NCT02620579
Document Date: 11/10/2016

A. Significance
A1.  Public Health Impact
Chronic pain is among the most prevalent, disabling, and costly conditions in the United States, and
throughout the world.  In 2011 the Institute of Medicine (IOM) Report - Relieving Pain in America: A Blueprint
for Transforming Prevention, Care, Education, and Research extensively documented chronic pain as a high
priority public health problem.1  Chronic pain affects 100 million people in the United States (U.S.) and
produces annual costs up to $635 billion, exceeding the prevalence and costs of heart disease, cancer, and
diabetes.1, 21 These costs are largely driven by musculoskeletal pain conditions. The burden of chronic pain is a
global concern; in 2012 the Global Burden of Disease Study identified musculoskeletal pain as a primary
contributor to years lived with disability internationally.22
Shoulder pain is a common musculoskeletal pain condition.  In the IOM report, the shoulder was the 5th 
most frequently reported pain site (estimated at 9.0% of all US adults over age 18).1  Other estimates of 
shoulder pain prevalence document high rates, including 1-year prevalence rates from 5 – 47% 23, 24 and point 
prevalence rates from 14 – 21%.25, 26 Shoulder pain is characterized by poor outcomes and resulting disability. 
For example, in one cohort 40% of the individuals did not report full recovery at 1 year after new onset of 
shoulder pain.27  Among those with shoulder pain, 17.7% had difficulty with basic daily activities while 21.4% 
had difficulty with complex daily activities.1  These data clearly demonstrate the public health significance 
of musculoskeletal shoulder pain and justify the study of interventions that have the potential to 
ameliorate shoulder pain and reduce this burden to individuals and society.    
A2.  Priority for Pain Relief in the United States 
Preventing the development of chronic pain conditions is a high priority initiative for improving patient care.  
The importance of this issue is highlighted in an NIH Program Announcement (PA-13-118:  Mechanisms, 
Models, Measurement, & Management in Pain Research) and the aforementioned IOM report. Unfortunately, 
current knowledge of mechanisms involved in the transition to chronic pain is limited, which decreases options 
for effective treatment of pain.  Studies that target validated risk factors that confer increased risk of 
experiencing chronic pain provide a unique opportunity to vertically advance the field.  Indeed, interventions 
tailored to specific risk factor characteristics (i.e. personalized medicine) hold great promise in reducing the 
impact of chronic pain.28, 29  The proposed work is significant because it will address this high priority 
issue by investigating efficacy and mechanisms of a personalized pain intervention that targets a 
subgroup at high-risk for experiencing chronic shoulder pain.     
A3.  Significance of Renewal Application 
The ultimate goal of our line of research is to develop personalized interventions for musculoskeletal 
pain.  Personalized medicine via identification of genetic risk factors has been successfully implemented for 
select areas of cardiac medicine30-33 and oncology.34-36  However, similar successes have not been achieved 
for pain treatment when focusing on genetic risk factors alone.29  Because of their complex biopsychosocial 
etiologies, personalized interventions for chronic pain conditions will depend on identification of genetic factors 
in combination with psychological, environmental, and/or social risk factors.28  This multiple risk factor 
approach served as the foundation for our work in the initial funding period.  We made significant progress 
toward our ultimate goal by validating a high-risk subgroup comprised of psychological and genetic 
factors that predicted pain outcomes in pre-clinical and clinical cohorts.   
This renewal application extends and translates this work by determining efficacy and mechanisms of 
personalized interventions targeting the genetic and psychological factors that make up the high-risk subgroup. 
We will use a validated pre-clinical model in the renewal application because it controls the injury mechanism 
and allows for high treatment fidelity.  The pre-clinical model also allows us to determine how underlying 
changes in molecular processes, psychological factors, and pain sensitivity regulation are associated with pain 
relief.  Furthermore this pre-clinical model has an established link to a post-operative clinical model.  In the 
renewal application we propose a study that will provide proof of principle that personalized pain 
interventions favorably alter outcomes and mechanisms for individuals that, without the personalized 
intervention, would go on to develop chronic shoulder pain.    

B.  Innovation  
Several aspects of the Biopsychosocial Influence on Shoulder Pain (BISP) design are innovative.  BISP follows 
the structure described by Diatchenko et al28, 37 for investigating risk factors contributing to the development of 
chronic musculoskeletal pain conditions.  Figure 1 graphically depicts the BISP conceptual model, which 
focuses on genetic and psychological factors as contributing to pain outcomes in parallel pre-clinical and 
clinical cohorts.  From the outset, genetic and psychological factors were a priori selected based on their 
potential to be targets of personalized interventions in future studies.  Thus, the original intent of BISP was to 
transition from predictive to intervention phases, pending direction provided by data generated in the initial 
funding period.  Additional innovative aspects of BISP are highlighted below.     
In the initial funding period we identified a 
human pre-clinical model that successfully 
translated to a clinical model of pain.  This is 
innovative 
because 
nonhuman 
pre-clinical 
models often face difficulties in translating to 
clinical pain populations.38, 39  We explored an 
alternate route for translation by inducing 
shoulder pain in healthy human subjects 
through controlled muscle injury that follows a 
fatiguing exercise protocol, referred to as 
“exercise-induced injury” in this proposal.  This 
pre-clinical model was selected because it had 
high translational potential for a clinical model 
of post-operative shoulder pain.19, 40 This was 
attributed to: 1) ability to induce muscle injury, 
inflammation, and pain in a specific anatomical 
region of the shoulder consistent with common 
surgical procedures (i.e. rotator cuff) and 2) 
pain responses monitored over several days 
which is likely a better clinical proxy than other 
transient induced pain options.41-43  Importantly, 
a high-risk subgroup based on genetic and 
psychological risk factors predicted heightened 
pain responses in both the pre-clinical exercise-
induced injury model and 12-month outcomes 
in the clinical post-operative model (in review).  
This translational success across pain models 
provides confidence that additional findings from our pre-clinical model will continue to have clinical relevance.   
 
The methodology in the renewal application represents an innovative approach to investigating 
personalized interventions for pain relief.  Personalized pain relief is often evaluated by identifying 
responder subgroups in a post-hoc manner and determining baseline characteristics predictive of a positive 
outcome.44  These studies lack experimental design features (e.g. randomization, precise treatment 
application) that allow for causality and typically fail to include a priori hypotheses regarding variables that will 
predict treatment response.  In the renewal application we will include an a priori identified high-risk subgroup 
validated during the initial funding period. We will use an experimental design to determine the efficacy of a 
personalized intervention matched to the genetic and psychological characteristics of the high-risk subgroup.  
Additional innovation comes from comparing combined personalized interventions (i.e. pharmaceutical and 
psychological) to each individual intervention (i.e. pharmaceutical or psychological) and a combined placebo 
condition.  In clinical studies pharmaceutical and psychological interventions are not typically investigated 
together in such a systematic manner, yet knowing the efficacy of a combined personalized intervention 
compared to different non-personalized conditions is imperative to drive understanding of what the “active” 
ingredients of the personalized intervention are.  In addition we will be measuring key processes that contribute 
to pain relief to determine underlying mechanisms within the same study.  Moreover, use of our pre-clinical 
model makes it feasible to prescreen participants to identify and target the high risk subgroup for enrollment.  
This provides far greater efficiency in the research design and is directly relevant to subsequent clinical 
investigations that will focus on improving post-operative outcomes for this high risk subgroup.   
 
Figure 1.  Biopsychosocial Influence on Shoulder Pain Conceptual Model  
BISP included: 1) a priori determined genetic and psychological risk factors for 
experimental pain sensitivity and clinical outcomes and 2) parallel investigation 
in pre-clinical and clinical cohorts.  Dark lines represent the hypothesized 
pathways that the genetic and psychological factors influence. Dotted lines 
represent direct pathways that were tested as competing hypotheses. The 
shaded bi-directional line indicates that minimal associations between genetic 
and psychological factors were observed. 

 
In summary, the renewal application for BISP offers many innovative aspects that make it likely to produce 
novel and important findings regarding efficacy and mechanisms of personalized interventions for pain relief. 
The information generated will vertically advance the field and also be vital in planning a follow-up clinical trial 
investigating personalized interventions to improve post-operative shoulder pain outcomes.           
 
Progress During the Initial Funding Period    
We completed pre-clinical exercise-induced shoulder injury (n = 190) and clinical post-operative shoulder pain 
(n = 150) cohort studies.  We have presented findings at national (n = 4) and international (n = 3) scientific 
conferences and disseminated results in high quality journals (n = 11 published, with n = 3 review).  We made 
notable progress towards our overall goal of developing personalized musculoskeletal pain interventions by 
identifying and validating a high-risk subgroup comprised of COMT genotype and pain catastrophizing.  This 
high-risk subgroup predicted: a) heightened pain responses following exercise-induced shoulder injury, and b) 
poor post-operative shoulder pain outcomes.  Below is a summary of key findings supporting our renewal:    
  
Exercise-Induced Shoulder Injury as a Pre-Clinical Model for Clinical Post-Operative Shoulder Pain:  The use 
of exercise-induced injury in humans was motivated by the difficulties and challenges with non-human animals 
as pre-clinical models in pain research.38, 39  One feature enhancing the translational potential of exercise-
induced injury is that it produces prolonged pain (mean days = 6.1, sd = 1.8), which is unique among 
experimental methods of inducing pain in humans (where duration is measured in seconds or minutes).41-43 
This is important because long duration is the defining characteristic of chronic pain. Furthermore, there was 
overlap in pain intensity and disability reports between the pre-clinical and clinical participants’ pre-operative 
ratings (Figure 2).  Additional evidence supporting this pre-clinical model came from analyses reported in the 
peer-review literature regarding similarities in endogenous pain modulation45, 46 and that a specific 
psychological factor, pain catastrophizing, was a predictor of pain outcomes for both cohorts.16, 47 These data 
supported the validity of this pre-clinical model and provided direction for future analyses.    
 
Interactions Between Genetic and Psychological Factors:  A primary aim in the initial funding period was to 
examine whether pain modulatory or pro-inflammatory genes interacted with pain-related psychological factors 
to predict phenotypes in the pre-clinical cohort (see previous Figure 1 for details).  The specific shoulder 
phenotypes studied were average and peak pain intensity, average and peak upper-extremity disability, and 
duration of shoulder pain.  Our findings revealed multiple interactions between genetic and psychological 
factors that improved prediction beyond either factor alone.19, 40 Two examples from these analyses are 
depicted in Figure 3 below.  These findings represent important progress during the initial funding 
period because they: 1) supported the conceptual foundation and primary aims of BISP, and 2) 
identified specific interactions between genetic and psychological factors that were further 
investigated as risk subgroups.   
 
 
  
 
         Exercise 
 
Surgical   
 
        Exercise 
 
Surgical  
 
Figure 2. Pain Intensity and Disability Overlap for Pre-Clinical (Exercise) and Clinical (Surgical) Shoulder Pain Models 
Pain (left panel) and upper-extremity disability ratings generated following exercise-induced injury were comparable with lower levels of pre-
operative pain and disability ratings from the surgical cohort when means are compared.  The entire range of pain and disability ratings 
demonstrated approximately 75% overlap between the two cohorts.   

Risk Subgroup Identification and Validation: The data presented in this section are currently in review.  
We a priori selected SNPs from COMT, AVPR1A, IL1B, and TNF/LTA region genes and psychological 
constructs (fear of pain, catastrophizing) represented as interaction terms in the previous analyses, and 
investigated whether risk subgroups comprised of these factors had prognostic value.  A subgroup approach 
was taken because it was more amenable to identifying individuals for personalized interventions in 
comparison to regression focused approaches. In these analyses, we first identified the high-risk subgroups in 
the pre-clinical model and then validated these subgroups in the clinical model. Hence, any risk subgroup 
that was predictive in both models would be considered a robust marker for identifying increased risk 
for the development of persistent shoulder pain, and an indication that the risk subgroup was 
appropriate for developing personalized pain interventions.  In the pre-clinical model, subgroups were 
identified based on prediction of heightened pain responses to muscle injury.  A “heightened response” was 
operationally defined as a peak pain intensity rating of ≥ 7/10 or pain that continued for at least 7 days 
(expected response is 4-5 days).  Eight genetic and psychological combinations were considered from the 
selected potential risk factors. Only the subgroups comprised of a COMT SNP for high pain sensitivity (rs6269) 
and 1) pain catastrophizing or 2) fear of pain predicted heightened pain response in the pre-clinical model 
(Table 1, indicated in bold font).   
 
In the clinical model 
these same high-risk 
subgroups 
were 
predictive of operative 
shoulder 
pain 
outcomes. 
 
Further 
analysis of the high 
risk 
subgroups 
accounting for age, 
sex, race, comorbid 
depressive symptoms, 
rotator cuff tear size, 
medication status and 
diplotype for COMT 
indicated 
that 
the 
high-risk 
subgroup 
of 
pain 
catastrophizing and 
COMT 
was 
the 
stronger predictor in 
the 
clinical 
model 
(Table 2).   
Table 1. Risk Subgroups for Heightened Pain Responses follow Exercise-Induced Injury 
 
High Risk Subgroup 
High Risk 
Low Risk 
P-Value 
N 
Percent 
Outcome 
N 
Percent 
Outcome 
Gene  
Outcome = Duration ≥ 7 days 
COMT  
rs6269 = 'AA' and FPQ≥15 
52 
36.5% 
130 
21.5% 
0.037 
 
rs6269 = 'AA' and PCS≥5 
42 
40.5% 
140 
21.4% 
0.013 
AVPR1A  
rs1042615 = 'AA' and FPQ≥15 
28 
35.7% 
158 
24.1% 
0.194 
  
rs1042615 = 'AA' and PCS≥5 
22 
36.4% 
164 
24.4% 
0.228 
 TNF/LTA  
rs2229094 = 'CT' and FPQ≥15 
64 
31.3% 
110 
23.6% 
0.272 
  
rs2229094 = 'CT' and PCS≥5 
50 
32.0% 
124 
24.2% 
0.291 
 IL1B  
rs1143627 = 'GG' and FPQ≥15 
41 
19.5% 
142 
26.8% 
0.346 
  
rs1143627 = 'GG' and PCS≥5 
72 
20.8% 
111 
27.9% 
0.280 
Gene  
Outcome = Peak BPI ≥ 7/10 
COMT  
rs6269 = 'AA' and FPQ≥15 
52 
48.1% 
130 
23.1% 
0.001 
 
rs6269 = 'AA' and PCS≥5 
42 
52.4% 
140 
23.6% 
<0.001 
AVPR1A  
rs1042615 = 'AA' and FPQ≥15 
28 
25.0% 
158 
29.7% 
0.610 
  
rs1042615 = 'AA' and PCS≥5 
22 
27.3% 
164 
29.3% 
0.847 
 TNF/LTA  
rs2229094 = 'CT' and FPQ≥15 
64 
25.0% 
110 
34.5% 
0.189 
  
rs2229094 = 'CT' and PCS≥5 
50 
24.0% 
124 
33.9% 
0.203 
 IL1B  
rs1143627 = 'GG' and FPQ≥15 
41 
31.0% 
142 
29.3% 
0.834 
 
rs1143627 = 'GG' and PCS≥5 
72 
31.5% 
111 
31.6% 
0.735 
 
  
 
         
 
Figure 3. Genetic and Psychological Interactions for Shoulder Pain  
Left Panel - for individuals with the high pain sensitive COMT diplotype, pain catastrophizing was a stronger predictor of average shoulder disability 
compared to those with the low pain sensitive diplotype  
Center and Right Panels - Analysis of the pro-inflammatory genes identified that the combination of a high-risk TNF/LTA region SNP and 
depressive symptoms improved prediction of average pain intensity and shoulder pain duration compared to those with the low risk SNP. 

Table 2.  Risk Subgroup Prediction of 12 Month Post-Operative Pain Recovery Outcome   
 
FPQ Subgroup 
 
PCS Subgroup 
 
Hazard Ratio 
 
95% CI   
p-value  
 
Hazard Ratio 
 
95% CI   
p-value  
 
COMT rs 6269 
Unadjusted model   
0.69 
0.44 – 1.07 
0.096 
 
0.51 
0.31 – 0.84  
0.009 
Partially adjusted model  
0.66  
0.42 – 1.05  
0.077 
 
0.53 
0.32 – 0.88  
0.013 
Fully adjusted model  
0.61  
0.37 – 1.00 
0.050 
 
0.44  
0.25 – 0.77  
0.004 
 
COMT Diplotype 
Unadjusted model   
0.69 
0.45 – 1.07 
0.095 
 
0.52 
0.32 – 0.83  
0.006 
Partially adjusted model  
0.68  
0.43 – 1.08  
0.100 
 
0.56 
0.34 – 0.92  
0.021 
Fully adjusted model  
0.64  
0.40 – 1.04  
0.072 
 
0.46  
0.27 – 0.80  
0.006 
Partially adjusted model was adjusted for demographics (age, sex, race); Fully adjusted model was adjusted for 
demographics, depressive symptoms, medications, and rotator cuff tear size. 
Transition to Renewal Application:  The validation of a robust high-risk subgroup comprised of COMT 
variation for high pain sensitivity and pain catastrophizing was the culminating finding from the initial 
funding period and provided clear direction for the renewal application.  Now BISP will transition to an 
intervention phase (Figure 4), using the pre-clinical model to determine the mechanisms and efficacy of 
personalized pain interventions matched to the genetic and psychological characteristics of the high-risk 
subgroup. Our ultimate goal is to conduct a randomized clinical trial in patients undergoing post-operative 
shoulder pain.  However, we believe a clinical trial would be premature at this point, as there remains a clear 
need for a pre-clinical study to establish proof of principle for efficacy and identify mechanisms of pain relief in 
this high risk subgroup before a highly resource-intensive clinical trial could be justified.  Very few treatment 
models for personalized pain interventions exist28, 29; therefore, this renewal application represents a significant 
advance in moving towards the reality of personalized treatments for musculoskeletal shoulder pain based on 
established genetic and psychological risk factors.  
This study will strongly impact the field by 
determining if individuals at high genetic and 
psychosocial risk for heightened response from 
shoulder injury respond favorably to personalized 
interventions matched to the characteristics of the 
risk subgroup.  Moreover, we will determine the 
relevant psychological, physiological, and pain 
sensitivity regulation mechanisms involved in pain 
relief.   
 
C.  Approach   
C1. Rationale 
The optimal theorized match for the identified 
high-risk 
subgroup 
is 
a 
combination 
of 
personalized pharmaceutical and personalized 
psychological interventions.  This combined 
intervention 
versus 
a 
combined 
placebo 
condition is the primary comparison of interest 
for this study.  We also will evaluate the individual 
effect of both the pharmaceutical and the 
psychological intervention.  Such comparisons will 
provide important information on whether the active 
portion of the combined personalized intervention is 
truly BOTH pharmaceutical and psychological 
components, or whether one component is 
sufficient for effective pain relief to occur.   
 
The high-risk subgroup is characterized by COMT 
genotype. COMT is a ubiquitously expressed 
detoxifying enzyme involved in a number of 
important 
biochemical 
pathways, 
particularly 
metabolism of catecholamines.48 COMT encodes a 
 
Figure 4. Biopsychosocial Influence on Shoulder Pain (BISP): 
Transition to Intervention Phase.  The top panel depicts the 
approach implemented during the initial funding period. The 
bottom panel depicts the proposed approach in this application. 

membrane-bound form that is 50 residues longer at the amino terminus than the soluble form and the relative 
levels of each appear to have temporal and tissue specificity.  In the initial funding period we found evidence 
for SNP rs6269 as a risk group predictor, consistent with a previous study that documented reduced COMT 
enzyme activity and increased pain sensitivity with the “A” allele at rs6269.49  In additional analyses of the 
clinical cohort we considered the established COMT 4-SNP pain sensitivity haplotype2, 50 for the genetic 
subgroup component and similar results were obtained (Table 4). However the rs6269 SNP was the stronger 
predictor in the pre-clinical cohort which may have been due to the diplotype grouping, underlying stratification 
in the subject cohort, or it might indicate that this SNP is carrying more of the effect in this risk subgroup.  
Specifically, rs6269 is in the promoter region of the soluble isoform of the gene, and thus could theoretically 
affect expression of the soluble form.  Alternatively, SNP rs6269 can be a genetic marker that differentiates 
COMT haplotypes coding for high activity enzyme variants from lower activity variants, consistent with other 
studies reporting an association with rs6269 SNP in general neurological51, 52 and pain-specific53 phenotypes.  
Regardless of the specific mechanisms involved, the genetic contribution of this risk subgroup appears to be 
diminished ability to modulate pain due to low COMT enzyme activity.  Consistent with a biopsychosocial 
framework for pain we also considered psychological factors and pain catastrophizing as the other part of the 
validated high-risk subgroup.  Pain catastrophizing is a maladaptive coping style comprised of magnification, 
rumination, and helplessness beliefs that perpetuate the experience of musculoskeletal pain.12  In studies from 
the initial funding period a genetic predisposition for low COMT enzyme activity and a coping approach 
consistent with pain catastrophizing was predictive of heightened pain responses and poor clinical outcomes.  
The consistent nature of these findings in separate cohorts lends credence to the notion that this particular risk 
subgroup is robust because it has strong theoretical and empirical evidence for its relevance in predicting 
chronic shoulder pain.  Therefore, we will address these risk factors by implementing a pharmaceutical 
intervention to counter effects of decreased COMT enzyme and a psychological intervention to 
address the impact of pain catastrophizing.   
 
C2. Overview  
Potential subjects will be screened and those meeting the high-risk criteria will be randomized into intervention 
groups. Treatment conditions will be administered for four consecutive days and statistical analysis will 
determine whether the combined personalized intervention group experienced shorter shoulder pain duration, 
lower peak pain intensity, or decreased upper-extremity disability (Aim #1) and determine which molecular, 
psychological, and pain sensitivity regulation mechanisms are associated with pain relief (Aim #2).  
 
C3.  Procedures  
An overview of BISP study procedures is presented in Figure 5, and then described in more detail.  
Figure 5. BISP Timeline and Study Procedures 
Risk 
Subgroup 
Screening. 
We 
propose 
to 
enroll 
448 
high-risk 
participants, 
which 
will 
require 
prescreening 
approximately 
3,000 
people.  In order to accomplish this 
we will conduct quarterly large-scale 
screenings on campus and in the 
local 
community 
(e.g. 
at 
local 
shopping malls, supermarkets, and 
community events) on a quarterly 
basis.  We anticipate screening at 
least 200 people at each event for the 
first 4 years of the award (15 events 
total).  At each screening, after 
providing 
informed 
consent, 
the 
participant 
will 
complete 
a 
brief 
screening questionnaire to determine 
eligibility and will be asked for 
permission to recontact.  Members of 
the BISP team (Drs. Diatchenko and 
Fillingim) have prior experience on 
screening this volume of participants 

through their work on the Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) study.54   
Eligibility will be determined from established inclusion and exclusion criteria from our initial funding period that 
establish appropriateness for the exercise-induced injury protocol, now modified to account for the risks of 
administering propranolol.  Details of the inclusion and exclusion criteria are reported in the Human Subjects 
section.  If eligible, each participant will provide a saliva sample and complete the Pain Catastrophizing Scale 
(PCS), a 13-item, 4-point rating scale.55, 56 A small incentive ($5 gift card) will encourage participation.  We 
have had success with similar approaches in the past for OPPERA.   
 
High-risk subgroup status will be based on parameters predictive of poor pre-clinical and clinical shoulder pain 
outcomes in the initial funding period.  Specifically, subjects with PCS scores of 5 or greater and COMT 
genotype indicative of high pain sensitivity by rs6269 (i.e. “AA”) and will be designated as high-risk.  Those 
familiar with the PCS will notice that a score of 5 is not elevated for general or clinical populations. 
However, this cut-off is specific for those with the COMT high pain sensitivity variation, so it is lower 
than if a general cut-off score independent of the genotype was used.  To control costs, genotyping will 
be performed only in those individuals who exceed the PCS cutoff.  All genotyping will be performed by Dr. 
Wallace’s laboratory using techniques described in the initial funding period.19, 40 DNA for the screening will be 
initially extracted from saliva (buccal swab, using Gentra PureGene system) and quality and quantity will be 
verified with Nanodrop spectrophotometry. Screening will focus on the rs6269 genotype based on our outcome 
from the initial funding period.  Dr. Wallace’s lab has developed a rapid, inexpensive in-house genotyping 
system for this SNP, using PCR followed by BstBI restriction digestion of the PCR product, to specify alleles 
based on simple gel electrophoresis (with appropriate known-genotype controls for partial digestion).  Based 
on the lab’s extensive experience, DNA extraction and genotyping will be completed for each sample within 3 
days, so that eligible participants can be recontacted as soon as possible.  For participants in the full study, 
additional DNA will be extracted from leukocytes from blood (also established in the lab) and re-genotyped for 
rs6269 for quality control.  In addition, the other three established, linked, COMT SNPs will be genotyped 
(rs4633, rs4818, rs4680) to investigate the full range of individual SNP and haplotypes that previously been 
associated with pain sensitivity in other studies,2, 57 and our own studies.17-19, 40 This genotyping will be done in 
batches through the UF Pharmacogenomics Core using established TaqMan Genotyping assayswith 5% 
duplicates for quality control.  Any samples failing TaqMan will be genotyped in the Wallace lab by restriction 
digest or sequencing.  Hardy-Weinberg equilibrium analysis will be done, as well as COMT haplotyping.  
Subject DNA (and RNA extracted from leukocytes) will be stored in Dr. Wallace’s lab, in an IRB-approved 
tissue/data bank, available for future analyses per consent of each subject. Screening is necessary because 
the personalized intervention is designed for genetic and psychological makeup of the high-risk subgroup. 
Participants in the low risk subgroup are not further eligible, and collected data will be destroyed.  In the initial 
funding period 42/182 (23.1%) subjects were designated as high-risk. Therefore, screening 3000 individuals 
gives us an expected 690 eligible to recruit 448 participants (64.9%).  The enrollment rate for eligible subjects 
was much higher than 65% in the initial funding period, so we think this is a conservative estimate of the 
numbers that will need to be screened.        
 
Randomization.  There are reported sex differences in pain conditions,58, 59 and we have observed that females 
report higher pain sensitivity in our studies of shoulder pain.60 Sex differences in how COMT impacts pain 
sensitivity has also been described, with females having a stronger association with pain sensitivity for certain 
genetic variants.61 Therefore randomization will be balanced to ensure equal allocation for males and females 
in the different intervention groups (i.e. sex stratified).  The randomization scheme will be prepared by 
computer and completed prior to the start of the study.  After the randomization list is generated treatment 
assignments will be contained in sealed, numbered envelopes.  Envelopes will be opened in sequential order 
as each participant enters the study by research staff blinded to application of interventions (i.e. treatment 
assignment and allocation will be by different research personnel). We will randomize prior to muscle injury to 
ensure propranolol is absorbed by the system before muscle injury.  Propranolol administration before injury 
allows for any immediate pre-emptive effects on the molecular or pain sensitivity regulation measures to be 
detected during the baseline session (Figure 5).  This administration also matches when propranolol would be 
administered in a clinical model (i.e. pre-operatively) so that translational component will be maintained.  
 
Exercise-Induced Shoulder Injury.  Research personnel performing the muscle injury protocol will be blinded to 
randomization results. Subjects will undergo exercise-induced shoulder injury to the dominant arm.  The 

specific eccentric exercise fatigue protocol uses isokinetic equipment62-66 and is an established protocol from 
the initial funding period16, 19, 40 and other prior published studies.18, 67 The fatigue protocol will be performed 
prior to randomization to maintain blinding to prevent bias.  Briefly, shoulder fatigue will be induced using a Kin-
Com (Chattanooga, TN) isokinetic dynamometer. Subjects will be placed in a seated position, with shoulder 
straps applied to support the torso.  Then, the dominant shoulder will be placed in the scapular plane because 
this position has been associated with high test-retest reliability and has decreased impingement of the greater 
tuberosity under the acromion.62, 68  Maximum voluntary isometric contraction (MVIC) will be determined by 
having the subjects perform 5 repetitions of isometric shoulder external rotation.  Subjects will be asked to 
perform the contractions with maximal effort and given verbal encouragement during the contractions.  The 
MVIC will be determined by averaging peak force from the middle 3 repetitions.69, 70   
      
After MVIC is determined, subjects will complete eccentric/concentric external rotation repetitions to induce 
muscle fatigue and microtrauma. The first set of repetitions will be completed at 100 degrees/second to 
familiarize the subjects with the testing apparatus.  Then, the speed will be lowered to 60 degrees/second for 3 
sets of 10 repetitions that constituted the fatigue protocol.  After completing those repetitions, subjects will be 
re-tested to determine if they can generate more than 50% of their respective MVIC.  Previous research has 
indicated the inability to achieve 50% of initial peak MVIC is an indicator of muscle fatigue.63-66 If they are 
unable to achieve at least 50% of their MVIC, the fatigue protocol is terminated.  If they are able to generate 
more than 50% of their MVIC, subjects will perform additional sets of 10 repetitions at speeds of 45 
degrees/second.  This will be repeated until their peak force is less than 50% of the initial MVIC.  Subjects will 
be allowed to rest 30 seconds between sets and the total amount of work performed to reach muscle fatigue 
will be recorded.  The goal of the injury protocol is to induce delayed onset muscle soreness (DOMS) in the 
rotator cuff musculature.  Shoulder DOMS is a clinically relevant model because subjects experience increased 
pain intensity, loss of range of motion, inflammatory responses, altered proprioception, and the use of self-care 
behaviors.63, 64, 66, 71-75 Additional relevance of this model for post-operative shoulder pain was confirmed in the 
aforementioned studies from our initial funding period.   
Personalized Interventions. Pharmaceutical: Increasing evidence implicates β-adrenergic drive in the 
pathophysiology of chronic pain conditions.  Indeed, musculoskeletal pain conditions are associated with 
heightened catecholamine levels and increased sympathetic responses to stressors.76-78 Also, in rodents 
epinephrine produced a β-adrenergic receptor-mediated mechanical hyperalgesia.79 Additional evidence 
suggests that these pronociceptive effects of catecholamines can be reversed by blocking beta-adrenergic 
receptors.  For example, a single infusion of propranolol temporarily reduced clinical pain among individuals 
with temporomandibular disorder and fibromyalgia.80 Another study showed that pindolol, a medication that 
blocks both β-adrenergic and serotonin 1A receptors, reduced pain and tenderness in patients with 
fibromyalgia.81 Moreover, in rodents, propranolol has been found to decrease inflammation-evoked 
hyperalgesia in joint and muscle.82, 83 Catechol-O-methyltransferase (COMT), the enzyme encoded by COMT, 
metabolizes catecholamines, including epinephrine and norepinephrine.84 COMT genotypes associated with 
lower COMT activity have been associated with increased risk of musculoskeletal pain3, 85 and greater pain 
sensitivity.2, 57  Preclinical work from the laboratory of Dr. Diatchenko (a consultant to the current project) 
showed that COMT inhibition produced robust thermal and mechanical hyperalgesia, which was blocked by 
propranolol.9 Furthermore, clinical work from Dr. Diatchenko demonstrated that the analgesic effect of 
propranolol in people with orofacial pain was dependent on the subject’s COMT genotype – with greater 
analgesia observed in patients with a haplotype conferring low COMT activity.8 Our personalized 
pharmaceutical intervention is designed to be consistent with that finding. Thus, lower COMT activity leads 
to increased catecholaminergic activation of beta-adrenergic receptors, thereby increasing risk for and 
severity of musculoskeletal pain. Therefore, we hypothesize that due to its blockade of beta-adrenergic 
receptors, propranolol will be particularly effective at reducing pain in individuals with low COMT 
activity, such as for our high-risk group.  
The UF Investigational Drug Service will prepare long-acting propranolol (Propranolol LA) 60 mg to be 
administered orally in the Pain Clinical Research Unit once daily for the five days of the protocol.  This dose will 
provide a bioequivalent dose to that recently reported in a clinical study examining responses to propranolol 
among patients with TMD pain.8 The first dose will be administered prior to the exercise-induced shoulder 
injury to mimic pre-operative settings and to allow for immediate effects to be observed during the baseline 
session.  Subsequent doses will be applied at the beginning of each session. Cardiovascular response (i.e. 
ECG, HR and BP) will be monitored 60 minutes after drug administration by a research nurse.  The purpose of 

this monitoring is for safety (early identification of potential adverse events) and efficacy (demonstrate 
medication absorbed). These measures will be recorded by the research nurse in a blinded manner, and not 
made available to any other research personnel performing testing within that session, unless subject safety is 
a concern. These data will be used by the investigator team as a manipulation check to assure that propranolol 
absorption is occurring, and allow for adjustments to be made early in the protocol if not.   
 
Psychological: Dr. George has been involved with design of psychological interventions used in several low 
back pain clinical trials86-89 and co-authored a perspective on key principles in psychologically informed 
interventions for low back pain.20  These principles are not specific to the anatomical region of pain, for 
example there is a clinical trial of cognitive behavioral treatment for reducing catastrophizing in individuals with 
chronic headache.90 These same principles were used to design a psychological intervention for shoulder pain. 
There is consistent evidence that psychological influence on exercise-induced shoulder injury comes from 
pain-related fear, kinesiophobia, and pain catastrophizing,15, 16, 67 as has been reported for individuals with pain 
in other body regions.13, 14, 91, 92  Therefore, the psychological intervention will reduce these factors with special 
emphasis on pain catastrophizing since that was the factor in the subgroup and it has been established as an 
important therapeutic target for cognitive based interventions.93 Additional justification for a separate 
psychological intervention comes from an indication that propranolol alone did not improve psychological 
status for subjects with orofacial pain.8 The psychological intervention will be administered on Days 2-5 of the 
protocol since the intervention is predicated on the individual experiencing pain.  This approach also allows for 
immediate effects of propranolol to be determined in the baseline session. The first principle relates to 
cognitive restructuring through psycho-education,20 which will encourage activation by: a) reducing the 
threat of muscle injury; b) encouraging normal use of the shoulder and arm; and c) addressing specific 
concerns or misapprehensions expressed by the subject (e.g. concern that pain experienced with shoulder 
motion is a sign of re-injury).  The education approach will be scripted and structured so it is provided in a 
standardized manner for all subjects.  The second principle relates to cognitive restructuring through 
activity20 which will be graded exposure.  Briefly, graded exposure is a behavioral treatment appropriate for 
individuals that avoid activity due to fear of pain and catastrophizing. Graded exposure involves identifying an 
activity the subject is fearful of or threatened by, and then devising a movement program that gradually leads 
to being able to perform the activity.94  The progression of the movement program is hierarchically based so 
that when subjects have lessening of fear, more difficult movements are added.  Successful application of 
graded exposure for low back pain has been reported in pre-clinical settings95 and in our previous clinical 
trials.86, 96 There will be modifications made for shoulder pain.  For example for low back pain reaching or 
twisting are commonly avoided activities,95, 96 but subjects with shoulder pain have reported avoiding washing 
their hair. In this case the graded exposure program would initially encourage shoulder external rotation and 
elevation, first in protected ranges, and then in more elevated ranges that mimic washing hair.  Although the 
activity identified as avoidant will differ between subjects, the graded exposure approach to address this 
activity limitation will be scripted and structured so it is provided in a standardized manner for all subjects.   
 
Placebo Interventions. Pharmaceutical: Placebo pharmaceutical capsules will be prepared by the UF 
Investigational Drug Service to be visually indistinguishable from the active medication.  Placebo administration 
will be done in the same fashion as was described in the personalized pharmaceutical section to maintain 
blinding.  This includes the same timing for each session and monitoring of cardiovascular responses.       
  
Psychological:  The placebo psychological intervention will match the structure and administration of the 
personalized intervention with the participant remaining blinded to what is received. These components consist 
of general education and activity principles that did not change psychological measures in our low back clinical 
trials.87, 88 Since these principles are not specific to anatomical region, they are appropriate for use in this study 
of shoulder pain. The first principle relates to education which will enhance understanding of shoulder anatomy 
by reviewing: a) structure and arthrokinematics of the shoulder joint; b) muscle anatomy of the shoulder with 
emphasis on the rotator cuff; and c) potential pain generators in the shoulder.  The placebo component is an 
neducation approach that accounts for time spent with research staff and dissemination of knowledge relevant 
to the mechanism of muscle injury, but is devoid of the cognitive restructuring that characterizes the active 
psychological intervention. Thus, this education is not specific to issues that perpetuate pain 
catastrophizing and can be considered a placebo.  The second principle relates to activity which will be a 
general exercise program that encourages gradual return of shoulder movement.  Briefly, subjects will be 
instructed in a 24-hour rest period following the injury, then range of motion exercises, and finally muscle 

activation will be resumed through isometric exercise.  The progression of the exercise will be based on the 
time from muscle injury, with a progression each day anticipated.  The placebo component is that it is a 
generic, protocol based exercise program not specific to activity being avoided due to pain 
catastrophizing.  In this manner it accounts for time spent with research staff for general exercise or activity 
recommendations. The placebo psychological intervention will be scripted and structured so it is provided in a 
standardized manner for all subjects.   
     
Primary Outcome Measures.  The primary outcome measures were selected based on relevance to the clinical 
model and successful use in the initial funding period. Pain intensity ratings and self-report of upper-extremity 
disability will be used as primary outcome measures to determine efficacy for shoulder pain duration, peak 
shoulder pain intensity, and peak upper-extremity disability. These constructs have a conceptual link to 
chronic pain1 and therefore can be used to characterize the presence of persistent or continued pain 
following exercise-induced injury. The Brief Pain Inventory (BPI) will be used to measure pain intensity as it 
has been found to have good test-rest reliability over short intervals.97 The BPI consists of rating pain intensity 
on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain intensity imaginable).  The BPI 
asks subjects to rate current pain and pain at its worst, best and average over the past 24 hours.  To 
determine recovery, subjects will complete the BPI daily until they rated their current pain at 0/10 and 
their worst pain was rated less than 2/10.  The number of days it took to reach this recovery criterion 
will be recorded as duration of shoulder pain. The highest worst pain intensity recorded during recovery will 
be recorded as the peak shoulder pain intensity. The Disabilities of the Arm, Shoulder, and Hand 
Questionnaire (DASH) will be used to assess upper-extremity disability and we will continue to use a validated 
abridged version of the DASH (the QuickDASH) which consists of 11 functional items, with total scores ranging 
from 0 (not disability) to 100 (complete disability).98  We will use the QuickDASH because shoulder pain can 
also affect distal function of the arm and hand, and we wanted to obtain a global upper-extremity assessment.  
Similar to the BPI ratings, QuickDASH scores will be recorded daily until recovery and the highest score during 
this period will be recorded as peak upper extremity disability.  Another advantage of these measures is they 
are widely accepted as primary outcome measures in clinical studies, and were used as such in the initial 
funding period.  Therefore, these measures will allow for specific effect size estimates for a subsequent 
randomized clinical trial in post-operative shoulder pain.        
  
Secondary Outcome Measures. These measures represent underlying mechanisms that we hypothesize to be 
related to how the personalized interventions affect pain relief. These measures will be obtained at the same 
time each day (relative to the time of the initial shoulder injury) to avoid unwarranted variation. 
 
Molecular:  These measures will capture relevant inflammatory biomarkers. The low COMT activity of our high-
risk group results in increased catecholamine activity, which augments release of proinflammatory cytokines 
under conditions of stress.99-101 This catecholamine-evoked cytokine release can be attenuated by 
propranolol.99-102  Moreover, catastrophizing, which also characterizes our high-risk group, has been 
associated with greater increases in circulating proinflammatory cytokines following both acute pain103 and 
induction of pain-related negative emotions.104 Thus, we hypothesize that personalized pharmaceutical or 
psychological intervention will significantly attenuate cytokine levels, with the greatest reduction observed in 
the combined personalized intervention condition.  Moreover, because the increased pain evoked by COMT 
inhibition has been found to be mediated by increased circulating cytokines and reversed by blockade of beta-
adrenergic (β2 and β3) receptors,7 we further expect that the attenuation of cytokine release will be associated 
with the efficacy of our combined personalized intervention for reducing pain and disability. Thus, we plan to 
perform assays for several inflammatory cytokines, including IL1B, IL6, IL8, and TNFα at baseline, immediately 
after the exercise-induced injury, and at regular intervals (Figure 5).  All assays will be performed by the 
Metabolism and Translational Science Core of the Claude D. Pepper Older Americans Independence Center 
using commercially available kits with which they have extensive experience.  
 
Psychological: In addition to the aforementioned PCS, the Tampa Scale of Kinesiophobia which is an 11-item 
(TSK-11), 4 point rating scale to quantify avoidance and re-injury beliefs105, 106 and the Fear of Pain 
Questionnaire (FPQ-III) which is a 30-item, 5-point rating scale to quantify fear about specific situations that 
normally produce pain107-109 will be used to capture psychological processes.  Consistent with a fear-avoidance 
model of musculoskeletal pain,110 we hypothesize that the personalized psychological intervention will reduce 
these levels significantly via cognitive restructuring providing subsequent decreases in disability and pain.   

Pain Sensitivity Regulation: These measures characterize nervous system processing of standard stimuli so 
that central or peripheral sensitization states indicative of pain amplification can be detected.41, 43, 111  Pain 
amplification is important to account for separately because it is hypothesized as a precursor to chronic 
musculoskeletal pain conditions that can occur with or independent of the molecular and psychological 
measures.28 The potential contributors to pain amplification are multifactorial, therefore we hypothesize that the 
combined personalized intervention group will show the largest reduction in measures indicative of pain 
amplification. All pain sensitivity measures will be obtained by psychophysical sensory testing as per 
established protocols established from the initial funding period.45-47, 111 All stimuli will be delivered to bilateral 
upper extremities to allow for side to side comparisons.  Stimulation sites will be varied to prevent carryover 
effects due to local sensitization. The stimuli are to be applied by a research assistant blinded to intervention 
status who ensures proper application and the range of stimulus intensities to be used (30-54°C) will be 
presented beforehand to each subject.  All subjects will undergo a brief training with the stimuli to be tested.  
We have found this procedure to be useful because it familiarizes subjects with the stimulus range, tends to 
obviate range effects in psychophysical scaling, and helps alleviate subject anxiety about the upper limit of 
stimulus intensities to be used.  The research assistant will record patient visual analogue scale (VAS) 
response to each stimulus used. The VAS will consist of a 10 cm line whose endpoints are designated as 'no 
pain sensation' and 'the most intense pain sensation imaginable'.  In order to standardize the scaling 
instructions, standard instructions112 will be used for all subjects. The specific pain sensitivity regulation 
measures to be collected include suprathreshold heat pain responses, pressure pain threshold, and 
conditioned pain modulation. Exact parameters for these measures are explained in more detail in  
publications from the initial funding period.45-47, 111 These measures were selected because we expected them 
to be responsive to the combined personalized intervention and associated with pain relief.  For example, 
elevated suprathreshold heat pain responses normalized post-operatively in the clinical cohort46 and its 
changes were associated with improvements in post-operative shoulder pain and disability.113    
 
C4. Statistical Analysis Plan  
All statistical analyses will be performed using the SAS software, version 9 (SAS Institute Inc, 1996). Summary 
statistics will be provided for baseline measures by intervention groups to determine if randomization produced 
balanced groups.  Any group imbalance will be investigated further to determine if covariates should be 
considered. For Specific Aim #1, our primary analysis for efficacy will compare shoulder pain duration (i.e. 
number of days until subject rated their current pain at 0/10 and their worst pain was rated less than 2/10) 
across the four randomly assigned groups with the use of logistic regression. Consistent with the initial funding 
period, the primary outcome variable will be dichotomized based on duration of at least 7 days or not. There is 
an a priori plan to include age, sex, and race as covariates in this analysis, additional variables will be added 
as covariates only if imbalanced across groups and correlated with outcome measures. We anticipate very little 
missing data because this is a pre-clinical study, but any missing outcomes will be predicted by subject pain 
intensity trajectory plus baseline demographic factors.  The primary comparison between the combined 
personalized intervention and the combined placebo condition will be tested at the 0.05 significance level, 
while the other five between group contrasts will be tested using a step-down procedure.  For the other primary 
outcomes (peak pain intensity and upper-extremity disability as continuous measures) we will perform a similar 
analysis process (i.e. same considerations for post randomization imbalance, covariates, and missing data) 
with linear regression analysis to compare the four intervention groups. For Specific Aim #2, we will fit path 
models with predetermined orders to investigate the direct (intervention group) and indirect effects (through the 
mediating psychological, molecular, and pain sensitivity paths) of the randomly assigned condition on pain 
relief.  The combined placebo intervention will serve as reference group for these analyses. The total, direct 
and indirect mechanistic effects on pain duration (dichotomous) and peak pain intensity and upper-extremity 
disability (continuous) will be estimated and tested at the 0.05 significance level for the comparison of assigned 
conditions. Specifically, the total effect will be estimated and tested through a logistic regression for pain 
duration and a general linear model for peak pain intensity, both of which include the assigned intervention 
conditions as independent variables while controlling for participant age, sex, and race.  The direct effect will 
be estimated and tested with the use of the same models including the same independent variables, but 
controlling for mediating molecular, psychological, and pain sensitivity variables in addition to age, sex and 
race. The two regression models in the second step will reveal the contributions of the mediating 
psychological, molecular, and pain sensitivity variables on pain relief. On the other hand, the indirect effect will 
be calculated based on the difference between the total and direct effects.  In addition, we will conduct a third 

set of regression analyses to evaluate the effect of the assigned condition on the mediating variables which will 
determine which indirect paths are statistically significant.      
 
C4. Sample Size Estimate and Study Timeline  
A total of 448 high-risk subjects will be recruited. In the initial funding period we found that 40.5% of high risk 
subjects had pain duration ≥ 7 days while 21.4% of the low risk group had long duration (Table 1). In our power 
analysis, we assumed that 40% of the combined placebo group will have long pain duration (rate for high risk 
subgroup), while the rate for the combined personalized intervention group will be 20% (rate for low risk 
group).  Those with one personalized intervention were assumed to have 30% chance of having duration ≥ 7 
days. The planned sample size will enable us to have 80% power to detect the assumed differences across the 
four intervention groups and 91% power for the primary comparison between the combined personalized and 
the combined placebo interventions at a type-I error level of 0.05.  The overall BISP timeline is in Table 3.   
 
Table 3.  Timeline and Key Periodic Events for BISP      
C5. Potential Pitfalls and Alternative Approaches   
1) Feasibility of Proposed Sample Size. In the initial funding period we recruited 340 subjects.  There is 
potential for higher recruitment rate in this proposal because it involves only the exercise-induced injury cohort 
of healthy volunteers. Recruiting for the clinical cohort was much more time intensive. Drs. Diatchenko and 
Fillingim have experience in large scale recruitment from OPPERA54 and our planned screenings will generate 
sufficient high-risk participants. The protocol requires at least five days of participation from participants and we 
had an outstanding completion rate (189/190) during the initial funding period.  Therefore, retention and 
missing data are not expected to be a concern. If there is more missing data than anticipated we will account 
for it in our statistical analysis. 2) Lack of Shoulder Specific Intervention Pilot Data. Pilot data demonstrating 
effect sizes will be vital when proposing a clinical trial in the post-operative setting. This renewal proposal 
includes established pharamaceutical8 and psychological86 interventions that have demonstrated effects in 
clinical populations (orofacial and low back pain respectively) from studies conducted by members of this 
research team. We will monitor intervention responses for expected results on process variables and adjust the 
intervention components if indicated. 3) Low Risk Subgroup. Intervention effects for low risk subjects will be 
unknown, and these effects potentially have scientific interest.  However the pragmatic advantages of greater 
research design efficiency and direct relevance to clinical investigations justified focus on the high risk 
subgroup. 4) Exploratory Analyses. We intentionally presented a focused statistical analysis plan to determine 
the efficacy (Aim #1) and mechanisms (Aim #2) of the personalized interventions described in this proposal. 
We do acknowledge that response to these interventions may not be as predictable as we have hypothesized.  
In the unlikely event that the Aim #1 analyses indicate no group differences we will perform additional analyses 
to inform future research in this area. For example as already mentioned, there is potential for sex differences 
in pain sensitivity58-60 and COMT variant influence on pain sensitivity61 to impact study results.  We have 
accounted for this with stratified randomization based on sex and by a priori including sex as a covariate in 
primary analyses.  In the case of null findings, however, a specific exploratory analysis will determine if sex-
specific intervention effects occurred.  For Aim #2 other analyses will be more exploratory in nature (e.g. post-
hoc treatment responder) and will be enhanced by the storage of excess DNA, plasma, and RNA so additional 
genetic predictors and molecular mechanisms can be considered (assuming subjects consent for that use).  
 
C6. Summary and Future Research Directions  
Chronic musculoskeletal pain is a significant public health problem.  Since 2006 this talented, multidisciplinary 
team has been working to develop personalized musculoskeletal pain management options.  Renewal of this 
application will allow the important predictive work from the initial funding period to be transitioned to a high 
impact pre-clinical intervention study.  Ultimately, we hope that completion of the proposed study provides 
foundational data to substantially improve standard of care by identifying personalized interventions that offer 
pain relief for those most at risk for developing chronic shoulder pain.   
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Start 
Up  
Quarterly Meetings with Research Team   
Annual Progress Reports to Institutional Review Board, Data Safety Monitoring Body, and NIH  
 
Screening, Recruitment (annual rate = 96-120 participants), Intervention, and Follow Up  
 
 
Scientific 
Conference 
 
Scientific 
Conference 
 
Scientific 
Conference 
 
Scientific 
Conference 
 
Scientific 
Conference 
On Site 
Consult 
 
On Site 
Consult 
 
On Site 
Consult 
 
On Site 
Consult 
 
On Site 
Consult 
Analysis, 
Dissemination