Feasibility of Pain Informed Movement for People With Knee Osteoarthritis
Phase: NA
Conditions: Knee Osteoarthritis
Sponsor: McMaster University

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Title of Study:   
Feasibility of Pain Informed Movement for people with knee osteoarthritis  
  
Local Principal Investigator:   
Lisa Carlesso, PT, PhD, McMaster University, Hamilton, ON, Canada   
Clinicaltrials.gov protocol NCT04954586  
Date: December 7, 2022  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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Introduction  
Knee OA  
The prevalence of osteoarthritis (OA), of which the knee is the most affected joint, continues to 
increase1 and will significantly contribute to the use of healthcare resources, with an estimated 
1.45 trillion in healthcare costs by the year 20402 3. The severity of pain and its impact on function 
have been identified by people living with knee OA as two of the most important effects of the 
disease4, contributing to reduced quality of life3. Uncontrolled OA joint pain is associated with 
increased healthcare use, therefore improving pain management for OA in Canada may result in a 
significant healthcare expenditure savings of up to $488 billion3. Understanding the underlying 
mechanisms of OA pain is critical to effectively manage knee OA. The pain experience and its 
associated mechanisms in people with knee OA are known to be complex and multidimensional5, 
with alterations in pain signaling playing a major role in susceptibility to the development of 
persistent pain6 7, and non-responsiveness to guideline-based physiotherapy8. The current 
understanding of OA pain mechanisms is incomplete, resulting in limited pain management 
strategies.   
While it has become clear that pain sensitization is a common feature of knee OA,6 9-11 the role of 
descending modulation has been relatively less studied. Importantly, changes in nervous system 
sensitization to nociceptive input do not necessarily correlate with changes in self-reported pain, 
demonstrating that other factors modulating pain, a top down process, are at play12,13 14. Thought 
to have distinct neurophysiological mechanisms from exercise induced analgesia, descending 
modulation from the central nervous system can facilitate or inhibit nociception14 15. There is 
highquality evidence that suggests the use of a wide variety of exercise for people with knee OA 
can provide benefit in terms of a meaningful reduction in pain and improving quality of life, with 
modest improvements in physical function16 17. A recent review concluded that these effects are 
unlikely to be changed by future research and could be regarded as true. Current guidelines for 
conservative management of knee OA only recently acknowledged the potential benefit of mind 
body therapies, such as yoga or tai chi, with the latter receiving stronger support18-21. The 
conditional recommendation for yoga is largely due to the relative paucity of studies examining its 
effects and their low quality22. However, there is promising evidence to support that yoga for those 
with knee OA may improve pain intensity, function, and stiffness, compared to exercise and non-
exercise control groups with moderate to large effect sizes23 24. Considered safe for people with 
comorbidities, yoga has the additional benefit of addressing overall well-being through its 
combination of physical postures, breathing exercises, meditation, and relaxation20. It is 
hypothesized that this unique combination of activities modifies the experience of pain by 
regulating input into the many physiological systems involved in the modulation of nociceptive 
signals25. There is evidence that yoga exerts this effect partially by changing patients' cognitions by 
reducing pain catastrophizing26 and increasing pain acceptance modifying patients' relationships to 
their pain27, as well as improving psychological dimensions of disability, such as anxiety and fear of 
falling, even when compared to conventional exercise28. Furthermore, recent research has shown 
that prolonged yoga interventions can have significant influence on serum levels of Brain Derived 
Neurotrophic Factor (BDNF), a molecule known to play a role in central nervous system 
neuroplasticity29. There is a need to further our understanding of the impact on mind-body 
etchniques on pain mechanisms to inform the improvement of pain management among 
individuals with knee OA. This study will be the first to examine the feasibility and effects of a 

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focused pain informed movement program30 on this innate and integrated pain modulating 
pathway and will explore its impact on related BDNF and Nerve Growth Factor (NGF). Altered 
levels of BDNF and NGF have been observed in patients with knee OA31 32 and both are implicated 
in peripheral and central pain processes in OA, with the former involved in neuroplasticity and 
anti-NGF therapies being highly studied and considered for FDA approval29 33-35. Multiple reviews 
have indicated that medication used to inhibit NGF have improved function and decreased pain in 
patients with knee OA 36 37, but there is evidence that non-medical treatments such as 
conventional and mind-body exercise can also impact the levels of NGF as well as BDNF 38-40, 
indicating another potentially promising intervention.  
Objectives  
The aim of this study is to establish the feasibility of a pain informed movement program, that 
includes neuromuscular lower extremity strengthening exercises and pain neuroscience education 
aimed at improving pain modulation. The data collected will be used to inform a pilot and 
feasibility randomized controlled trial (RCT) prior to a multi site RCT to assess the program's 
effectiveness with the primary outcome of descending modulation as a mediator of change in pain 
severity.  
Research questions:  
1) Is the pain informed movement program feasible in terms of recruitment rate, treatment 
adherence, timelines, data collection procedures, patient follow-up and resources required? 2) 
Is the pain informed movement program feasible in terms of patient’s satisfaction and 
acceptability?  
  
Literature Review  
Impact of exercise on individuals with knee OA  
Exercise is regularly utilized as a first-line treatment for knee osteoarthritis, and its use is 
supported by high quality evidence to improve pain and function16. Multiple clinical practice 
guidelines for individuals with knee OA recommend the use of aerobic and strength training for 
the reduction of pain and improved physical function 20 41 Other studies have supported the use of 
a variety of exercise types in the management of OA17. A Cochrane review on exercise for knee OA 
identified a moderate effect size of exercise compared to no exercise in reducing pain and 
improving physical function42 and more recently a review of the available literature concluded that 
this moderate effect size was unlikely to be changed by future research 21. Thus, the evidence 
supporting the use of exercise in improving physical function and reducing pain for people with 
knee OA is well supported and widely accepted.  
Exercise leads to improved outcomes for knee OA via a number of pathways. Reductions in 
perceived pain can be explained in part by exercised-induced analgesia 43-46 which is thought to be 
mediated via numerous endogenous pathways, such as the endogenous opiate system43 along 
with the endocannabinoid system44. Furthermore, decreased nervous system sensitivity to noxious 
stimuli, measured via pressure pain thresholds seem to play a role in the decreased pain 
experience of individuals who engage in exercise45, as well as increased body awareness which 
may cause individuals to focus their attention on alternate body sensations than pain. This in turn 
may contribute to the diminished pain experience45. These mechanisms likely play a role in 
improved function and reduced pain along with the improved balance, muscle strength and 
flexibility that are conventionally associated with exercise46.  

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Impact of yoga on pain and function  
In recent years multiple guidelines for non-surgical management of knee OA have begun to include 
mind-body therapies, such as yoga or tai-chi, as conditional or core treatment recommendations20 
41. Structured yoga programs have been shown to result in decreased pain and improved function 
when compared to no exercise 47 and conventional exercise28. Two systematic reviews assessing 
the evidence for yoga treatment in people with knee OA found good evidence that yoga resulted 
in decreased pain and stiffness with moderate to large effect sizes 23 48. Both reviews indicated the 
need for future research to improve the methodological quality for studies on yoga effectiveness 
and to determine the mechanisms by which yoga leads to pain reductions in individuals with knee 
OA. Currently, there is evidence for involvement of numerous pathways involving multiple 
mechanisms. Some of those include changing patients' cognitions by reducing pain catastrophizing 
and increasing pain acceptance26, changing patients’ relationships to their pain27, as well as 
improving psychological dimensions of disability, such as anxiety and fear of falling, even when 
compared to conventional exercise28. There is also evidence that yoga may have a beneficial 
impact on inflammatory pathways and assist in reducing symptoms stemming from inflammatory 
disorders49. Additionally, evidence suggests that yoga may provide many of the same benefits of 
conventional exercise, including improved strength, flexibility and balance50 along with 
improvements in cardiovascular fitness that may exceed that obtained from conventional exercise 
alone51.  
Brain Derived Neurotrophic Factor  
BDNF is a neurotrophin that appears to play an important role in the central modulation of pain in 
adults52, and altered expression of BDNF is likely to play an important role in the pathophysiology 
of chronic pain53 54. Individuals with knee OA have been shown to possess altered levels of serum 
BDNF compared to healthy controls, indicating that BDNF may be implicated in the pain 
experience of patients with knee OA31. Thus, BDNF has been identified as a therapeutic target in 
the treatment of pain resulting from central sensitization34. One systematic review showed that 
exercise increased peripheral BDNF concentrations in elderly individuals with and without health 
impairments38 and another study reported that an aerobic exercise program in elderly women 
with knee OA resulted in increased BDNF plasma concentrations coinciding with improvements in 
walking distance and pain, suggesting that BDNF may mediate these improvements39. These 
results are encouraging, but further investigation is needed in order to determine the most 
appropriate interventions for achieving therapeutic BDNF levels38. Recently, a study assessing the 
effect on yoga on chronic low back pain found significant increase in serum BDNF levels with 
concurrent decreases in pain following a 12-week intervention29, indicating that yoga is another 
plausible exercise intervention that could impact BDNF levels.  
Nerve Growth Factor  
NGF is a neurotrophin known to play a critical role in the proper development of the nervous 
system55 56. Evidence indicates that NGF is also involved in the increased pain experience of many 
individuals via peripheral sensitization of nociceptive neurons57 58. Furthermore, NGF levels have 
been shown to be elevated in a wide variety of chronic pain conditions59 including knee OA32. As a 
result, anti-NGF therapies are being highly studied and considered for FDA approval35 as they have 
significant potential to decrease pain and improve function in individuals with OA that do not 
respond to conventional analgesics60. Multiple recent reviews have indicated that interventions, 
such as medication, used to inhibit NGF have resulted in decreased pain and improved function 

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and quality of life in patients with symptomatic OA36 37. Additionally, there is some evidence that 
acute moderate exercise can alter NGF levels in people with certain conditions40 indicating that 
alternative methods to medication could be explored.  
  
Ethical Considerations: This application has been reviewed by the Hamilton Integrated Research 
Ethics Board under Project #13461.  
  
Methods  
Study Design  
This pre-post test mixed methods study will assess the feasibility of a pain informed movement 
program. All included participants will be assessed at baseline and after the intervention.  All 
participants will also be invited to complete a satisfaction survey and take part in focus group 
interviews at the end of the program. These studies will be guided by the Conceptual Framework 
for Defining Feasibility61 and Pilot studies and the Standard Protocol Items: Recommendations for 
Intervention Trials.62  
Study Population  
A convenience sample of 15 adults will be sought and is adequate to evaluate the feasibility of the 
program63.  
Recruitment  
Participants will be recruited through the email lists of the McMaster Physical Activity Centre of 
Excellence (PACE) community. Recruitment posters will also be included in the McMaster Institute 
for Research on Aging (MIRA) newsletter. In addition, we will place postings on both PACE and 
MIRA social media pages.   
Participants   
Inclusion criteria:  
- 
≥40 years of age with a diagnosis of knee OA by a physician; OR  
- 
≥45 years of age having activity related knee joint pain with or without morning stiffness 
lasting 30 minutes (as per NICE criteria)  
- 
Having an average pain intensity of 3/10 on a numeric pain scale  
Exclusion criteria:  
- 
Cannot communicate in English;  
- 
Have inflammatory arthritis or other systemic conditions;   
- 
Have had lower limb trauma, surgery within the past 6-month;  
- 
Have participated in a similar knee OA exercise program in the prior 3-months;  
- 
Have used oral corticosteroids or had a corticosteroid injection in the index knee within 
6months prior to baseline assessment  
- 
Do not have regular access to the internet for viewing of educational videos  

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Intervention  
The proposed program will be an 8-week in-person group exercise program held twice weekly, in 
which participants will receive exercise instruction (60 minutes) and education (15min for the first 
4 sessions).  Home sessions will be facilitated by exercise handout sheets and access to video files 
to guide the participant through the exercises. The exercise component has been developed by a 
team member and will be delivered by an experienced yoga teacher. The education component 
will cover the following topics: The purpose of pain, basic neurophysiology of nociception and 
pain, common OA symptoms and risk factors, neurophysiological changes of pain, movement 
guidelines when pain persists, and self care techniques to impact neurophysiology and support 
moving with ease.  
Setting   
The in-person 8-week exercise program will be held twice weekly at McMaster University’s Physical 
Activity Centre of Excellence (PACE) located in the Ivor-Wynne Centre. Participants will complete 
the pain assessment, and have blood drawn at PACE by PACE staff who are certified phlebotomists.  
Pre-Assessment and Screening  
Potential participants will contact the research coordinator, who will explain the purpose of the 
study and determine participant eligibility. If eligible, participants will be sent a link to our online 
consent form using Limesurvey. Participants will also have the option to have this consent form 
mailed to them.  
Assessment  
As part of participation in the study, participants will be asked to attend an assessment at the 
beginning of the study, and once again upon completing the 8-week exercise program. Participants 
will undergo pain modulation (CPM) testing, and the 30 Second Sit to Stand Test to determine leg 
strength and endurance. Lastly, participants will have their blood drawn at the beginning and end 
of the study.   
Participants will then be asked to complete a series of questionnaires about their pain and mood. 
These will be completed via a link provided by the research coordinator for participants to 
complete on our online Limesurvey system. Alternatively, participants can have these 
questionnaires mailed to them to be complete and manually entered by the research coordinator. 
These questionnaires will be completed at the beginning and end of the study.   
Time Commitment  
The in-person assessments to complete the pain assessments and drawing of blood will take ~20 
minutes. Participants will be asked to complete the questionnaires before beginning the exercise 
sessions. Completion of these questionnaires will take ~20 minutes. Twice weekly exercise sessions 
will be an hour and 15 minutes in duration. Participants will be given instructions to complete 
these exercises at home at least one other time during the week for the same duration.   
In total, participants will complete an 8-week twice weekly exercise program at the university, one 
session at home and complete 2 series of questionnaires. The total time commitment for 
participants will be approximately 29 hours.   

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Outcomes  
Outcomes will be evaluated at 2 time points: at baseline and at the conclusion of the pain 
informed movement program (approximately 8 weeks).  
Feasibility Outcomes: Acceptability of the intervention (content, frequency, duration), burden of 
procedures (questionnaires, quantitative sensory testing, blood draws), recruitment rate, 
adherence rate, follow-up rate, self-reported adverse events, exercise completion (number and 
frequency completed). A priori success criteria will be used to determine feasibility.  
Participant characteristics: Age, sex, race, gender, education level, marital status, height, and 
weight will be collected.  
Pain modulation (CPM): CPM is an indicator of descending inhibitory pain modulation and a 
measure of the degree to which pain inhibits pain. Following recommended testing,64 first an 
ascending measure of pressure pain threshold (PPT) inducing a verbal pain rating of 3 out of 10 
will be evaluated at the anterior shin on the unaffected knee. Next a conditioning stimulus in the 
form of forearm ischemia will be applied to induce a minimum verbal pain rating of 5 out of 10 at 
the opposite volar forearm. The arm will be elevated to chest level with a blood pressure cuff 
around the middle of the upper arm. Systolic pressure will be determined. Next the cuff will be 
inflated to 20mmhg above systolic pressure and the participant will be asked to squeeze a stress 
ball until a pain rating of 5/10 is reported. Once pain rating is recorded, PPT at the anterior shin 
will be repeated as the cuff remains inflated.15 An index will be created by calculating the percent 
efficiency of CPM (%CPM) as PPT2/PPT1, multiplied by 100; whereby %CPM ≤ 100 indicates 
inefficient pain modulation.64 65 CPM testing has demonstrated good reliability intra-session ICC 
(0.75 - 0.85).65   
Pain intensity: Pain intensity will be measured with the Numeric Rating Scale, a unidimensional 
single item measure of pain intensity used in adult populations66. The average of three questions 
will be used: average pain intensity in the past 24 hours, past week, and worst pain in the past 24 
hours. Questions are rated on a an 11-point scale where patients select a rating between 0-10 with 
zero typically represents ‘no pain’ while 10 represents the ‘worst imaginable pain’67.  
Pain catastrophizing: Pain catastrophizing will be measured using the Pain Catastrophizing Scale68 
(PCS). The PCS is a 13-item self-reporting instrument for catastrophizing in the context of actual or 
anticipated pain, with higher scores indicating higher pain catastrophizing. Sub-scores for the three 
PCS dimensions (rumination, magnification, and helplessness) will also be calculated.   
Chronic pain self-efficacy: The Self-Efficacy for Managing Chronic Disease 6-item scale will be used 
to measure self-efficacy for chronic pain sufferers, with higher reported scores indicating higher 
self-efficacy69.  
Anxiety and depression: The Hospital Anxiety and Depression Scale (HADS) consists of 7 questions 
to measure anxiety and 7 questions to measure depression70. Higher scores represent increased 
severity in anxiety and depression symptoms. It is a brief and reliable measure of emotional 
distress in general and chronic populations including chronic pain and rheumatology.71 Average 
sensitivity and specificity is ≥ 0.80.  
Knee injury and outcomes: The Knee Injury and Osteoarthritis Outcome Score (KOOS) is a 
kneespecific instrument, used to assess self-reported opinions about patients’ knee and associated 
problems, while evaluating short-term and long-term consequences of knee injury. There are 42 

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items in 5 scored sub scales, of which two will be used: 1) pain, and 2) function in daily living 
(ADL). Scores range from 0-100 with zero representing extreme knee problems and 100 
representing no knee problems72. KOOS has adequate internal consistency (0.70-0.95) and 
construct validity in adults with knee OA.73 Multiple studies have determined convergent and 
divergent construct validity with comparison to several instruments including the subscales of 
SF36 and the Lysholm knee scoring scale.74  
Performance tests: The 30 Second Sit to Stand Test will be used to test leg strength and 
endurance75. Time will be measured with a handheld stop watch and recorded to the nearest 0.01 
secs for walking. The chair stand test is a measure of sit to stand activity and of lower extremity 
strength and balance. The maximum number of chair stand repetitions completed during a 30 
second interval will be noted along with use of any aids during testing. A standard chair height will 
be used for all participants (ICC 0.81-0.98).    
Blood analysis: A maximum of 5ml of blood will be drawn for analysis of BDNF and NGF. 
Measurement of BDNF and NGF requires 50µL of diluted plasma as per the ELISA kit.   
Exit Survey and Focus Group   
A satisfaction survey will be conducted at the end of the program to evaluate the a priori feasibility 
criteria. Participants who indicated upon initially consenting to the study that they would like to 
participate in a focus group, will be contacted. Consent for participation will be obtained in person, 
or participants will have the option to have this consent form emailed to them. Qualitative data 
collection will be used to explore participants experience and perceptions of the feasibility and 
acceptability of the program. The interview guide has been developed by patients and 
practitioners.  
Data Collection:  
A focus group will be conducted using audio or video recording (using Zoom), lasting between 
4560 minutes.  Transcripts will be available and will be reviewed for accuracy by participants. The 
qualitative software “Dedoose” will be used to manage, store, and analyze data.  
Methodological Rigor:   
Member checking (participants’ comments on any emergent themes), verification (researchers 
converge on recognizing “identical patterns” in the data), referential adequacy (providing enough 
quotes to ensure the findings fit the data) and maintaining an audit trail (records of decisions 
made), will be used to ensure methodological rigor.  
Statistical Analysis Plan (SAP) 
Feasibility of Pain Care Yoga: All quantitative analyses will be conducted using SPSS 26. Descriptive 
statistics will be used to report feasibility outcomes, and survey responses will be summarized 
(using descriptive statistics) to identify trends in patient-reported outcomes.   
Qualitative Interviews: Qualitative interviews will be analyzed using Thematic content analysis to 
identify suggestions for program modification. Line-by-line reading of the transcripts will be 
performed by the authors and thematic patterns will be explored. Once themes and patterns are 
identified, each meaningful segment of text will be assigned a conceptual code. When conceptual 
codes become saturated, authors will build pattern codes where specific dimensions of clinicians’ 
experiences will be clustered into recurring themes. Once the codes and themes are developed, 

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participant and clinician partners will be invited to contribute to blinded data analysis to broaden 
interpretations and provide feedback on the quotes and emergent themes.   
Impact  
Understand the underlying mechanisms of OA pain is critical to effective management, however 
our knowledge of knee OA pain mechanisms is incomplete given knee OA pain is complex and 
multidimensional5. The proposed study will be the first to examine the feasibility and effects of a 
focused pain informed movement program on this innate and integrated pain modulating pathway 
and will ultimately explore its impact on related Brain Derived Neurotrophic Factor (BDNF) and 
Nerve Growth Factor (NGF). Both are implicated in peripheral and central pain processes in OA, 
with the former involved in neuroplasticity and anti-NGF therapies being highly studied. The 
project will contribute to the clinical recommendations for management of OA pain using mind 
body therapies for clinicians across multiple sectors and will provide additional conservative pain 
management options for a disease that is expected to increase with the aging population. This 
study will lay the foundation to inform a multi-site RCT to assess the program's effectiveness with 
the primary outcome of descending modulation as a mediator of change in pain severity.  
Timeline  
Study recruitment and offering of the pain informed movement program will take place between 
January 2022 - September 2022. months. Meeting recruitment goals is highly feasible as based on 
approaching 500 members of PACE and cross-faculty MIRA institute, our recruitment rate will only 
need to be 3%.    
Plans for Knowledge Translation:  
The goal of our knowledge translation efforts will be to inform clinicians and researchers of the 
results of this study for research considerations and clinical recommendations. To do so, we will 
disseminate the results through journal article publications (e.g., Osteoarthritis and Cartilage and 
Arthritis Care and Research), peer review conferences (e.g., OARSI and Canadian Rheumatology 
Association), national professional organizations (Canadian Physiotherapy Association) and special 
interest groups such The Arthritis Society. We will also aim to use the results of this study to 
support the design of and application for funding a multicenter randomized controlled trial.  
  
  
  
References  
1. Vos T, Allen C, Arora M, et al. Global, regional, and national incidence, prevalence, and years 
lived with disability for 310 diseases and injuries, 1990&#x2013;2015: a systematic analysis for 
the Global Burden of Disease Study 2015. The Lancet 2016;388(10053):1545602. doi: 
10.1016/S0140-6736(16)31678-6  
2. Sharif B, Kopec JA, Wong H, et al. Distribution and Drivers of Average Direct Cost of  
Osteoarthritis in Canada From 2003 to 2010. Arthritis Care Res (Hoboken) 2017;69(2):243- 
51. doi: 10.1002/acr.22933 [published Online First: 2016/05/10]  
3. Arthritis Alliance of Canada. The impact of arthritis in Canada: Today and over the next 30 
years, 2011.  

Page 10 of 14  
4. Smith TO, Purdy R, Lister S, et al. Living with osteoarthritis: a systematic review and 
metaethnography. Scand J Rheumatol 2014;43(6):441-52. doi: 
10.3109/03009742.2014.894569 [published Online First: 2014/06/03]  
5. Hawker GA, Gignac MA, Badley E, et al. A longitudinal study to explain the pain-depression link 
in older adults with osteoarthritis. Arthritis Care Res (Hoboken) 2011;63(10):1382-90. doi:  
10.1002/acr.20298 [published Online First: 2010/07/28]  
6. Fingleton C, Smart K, Moloney N, et al. Pain sensitization in people with knee osteoarthritis: a 
systematic review and meta-analysis. Osteoarthritis Cartilage 2015;23(7):1043-56. doi:  
10.1016/j.joca.2015.02.163 [published Online First: 2015/03/10]  
7. Carlesso LC, Segal NA, Frey-Law L, et al. Pain Susceptibility Phenotypes in Those Free of Knee 
Pain With or at Risk of Knee Osteoarthritis: The Multicenter Osteoarthritis Study. Arthritis  
&amp; rheumatology (Hoboken, NJ) 2019;71(4):542-49. doi: 10.1002/art.40752 [published 
Online First: 2018/10/12]  
8. OʼLeary H, Smart KM, Moloney NA, et al. Pain sensitization associated with nonresponse after 
physiotherapy in people with knee osteoarthritis. Pain 2018;159(9):1877-86. doi:  
10.1097/j.pain.0000000000001288 [published Online First: 2018/05/26]  
9. Neogi T, Frey-Law L, Scholz J, et al. Sensitivity and sensitisation in relation to pain severity in 
knee osteoarthritis: trait or state? Ann Rheum Dis 2015;Apr;74(4):682-8. doi:  
10.1136/annrheumdis-2013-204191 [published Online First: 2013/12/20]  
10. Carlesso LC, Segal NA, Frey-Law L, et al. Pain Susceptibility Phenotypes in Those Free of Knee  
Pain with or at Risk of Knee Osteoarthritis: The Multicenter Osteoarthritis Study. Arthritis 
&amp; rheumatology (Hoboken, NJ) 2018 doi: 10.1002/art.40752 [published Online First: 
2018/10/12]  
11. Petersen KK, Graven-Nielsen T, Simonsen O, et al. Preoperative pain mechanisms assessed by 
cuff algometry are associated with chronic postoperative pain relief after total knee 
replacement. Pain 2016;157(7):1400-6. doi: 10.1097/j.pain.0000000000000531 [published 
Online First: 2016/06/23]  
12. Skou ST, Roos EM, Simonsen O, et al. The efficacy of non-surgical treatment on pain and 
sensitization in patients with knee osteoarthritis: a pre-defined ancillary analysis from a 
randomized controlled trial. Osteoarthritis Cartilage 2016;24(1):108-16. doi:  
10.1016/j.joca.2015.07.013 [published Online First: 2015/08/05]  
13. Edwards RR, Dolman AJ, Martel MO, et al. Variability in conditioned pain modulation predicts 
response to NSAID treatment in patients with knee osteoarthritis. BMC Musculoskelet Disord 
2016;17:284. doi: 10.1186/s12891-016-1124-6  
14. Rice D, McNair P, Huysmans E, et al. Best Evidence Rehabilitation for Chronic Pain Part 5:  
Osteoarthritis. Journal of clinical medicine 2019;8(11) doi: 10.3390/jcm8111769  
[published Online First: 2019/10/28]  
15. Yarnitsky D. Role of endogenous pain modulation in chronic pain mechanisms and treatment.  
Pain 2015;156 Suppl 1:S24-31. doi: 10.1097/01.j.pain.0000460343.46847.58 [published 
Online First: 2015/03/20]  
16. Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the knee: a Cochrane 
systematic review. Br J Sports Med 2015;49(24):1554-7. doi: 10.1136/bjsports-2015- 
095424 [published Online First: 2015/09/26]  
17. Anwer S, Alghadir A, Brismée JM. Effect of Home Exercise Program in Patients With Knee 
Osteoarthritis: A Systematic Review and Meta-analysis. J Geriatr Phys Ther 2016;39(1):38- 
48. doi: 10.1519/jpt.0000000000000045 [published Online First: 2015/02/20]  

Page 11 of 14  
18. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis 
Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee.  
Arthritis & Rheumatology 2020;72(2):220-33. doi: https://doi.org/10.1002/art.41142  
19. Fernandes L, Hagen KB, Bijlsma JW, et al. EULAR recommendations for the nonpharmacological 
core management of hip and knee osteoarthritis. Ann Rheum Dis 2013;72(7):1125-35. doi: 
10.1136/annrheumdis-2012-202745 [published Online First: 2013/04/19]  
20. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management 
of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 2019;27(11):1578- 
89. doi: 10.1016/j.joca.2019.06.011 [published Online First: 2019/07/07]  
21. Verhagen AP, Ferreira M, Reijneveld-van de Vendel EAE, et al. Do we need another trial on 
exercise in patients with knee osteoarthritis?: No new trials on exercise in knee OA. 
Osteoarthritis Cartilage 2019;27(9):1266-69. doi: 10.1016/j.joca.2019.04.020 [published Online 
First: 2019/06/21]  
22. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis 
Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee.  
Arthritis Care Res (Hoboken) 2020;72(2):149-62. doi: 10.1002/acr.24131 [published Online 
First: 2020/01/08]  
23. Kan L, Zhang J, Yang Y, et al. The Effects of Yoga on Pain, Mobility, and Quality of Life in Patients 
with Knee Osteoarthritis: A Systematic Review. Evid Based Complement Alternat Med 
2016;2016:6016532. doi: 10.1155/2016/6016532 [published Online First: 2016/10/26]  
24. Lauche R, Hunter DJ, Adams J, et al. Yoga for Osteoarthritis: a Systematic Review and 
Metaanalysis. Curr Rheumatol Rep 2019;21(9):47. doi: 10.1007/s11926-019-0846-5 [published 
Online First: 2019/07/25]  
25. Pearson N, Prosko S, Sullivan M, et al. White Paper: Yoga Therapy and Pain-How Yoga Therapy 
Serves in Comprehensive Integrative Pain Management, and How It Can Do More. Int J Yoga 
Therap 2020;30(1):117-33. doi: 10.17761/2020-d-19-00074 [published Online First: 
2020/05/16]  
26. Curtis K, Osadchuk A, Katz J. An eight-week yoga intervention is associated with improvements 
in pain, psychological functioning and mindfulness, and changes in cortisol levels in women 
with fibromyalgia. J Pain Res 2011;4:189-201. doi: 10.2147/jpr.S22761 [published Online First: 
2011/09/03]  
27. Tul Y, Unruh A, Dick BD. Yoga for chronic pain management: a qualitative exploration. Scand J  
Caring Sci 2011;25(3):435-43. doi: 10.1111/j.1471-6712.2010.00842.x [published Online 
First: 2010/11/10]  
28. Cheung C, Wyman JF, Bronas U, et al. Managing knee osteoarthritis with yoga or 
aerobic/strengthening exercise programs in older adults: a pilot randomized controlled trial. 
Rheumatol Int 2017;37(3):389-98. doi: 10.1007/s00296-016-3620-2 [published Online First: 
2016/12/04]  
29. Lee M, Moon W, Kim J. Effect of yoga on pain, brain-derived neurotrophic factor, and serotonin 
in premenopausal women with chronic low back pain. Evid Based Complement Alternat Med 
2014;2014:203173. doi: 10.1155/2014/203173 [published Online First: 2014/08/15]  
30. Pearson N. Pain Care Yoga - Pain Care U [April 29 2021]. Available from:  
https://paincareu.com/pain-care-yoga/.  
31. Simao AP, Mendonca VA, de Oliveira Almeida TM, et al. Involvement of BDNF in knee 
osteoarthritis: the relationship with inflammation and clinical parameters. Rheumatol Int 
2014;34(8):1153-7. doi: 10.1007/s00296-013-2943-5 [published Online First: 2014/01/09]  

Page 12 of 14  
32. Stoppiello LA, Mapp PI, Wilson D, et al. Structural associations of symptomatic knee 
osteoarthritis. Arthritis Rheumatol 2014;66(11):3018-27. doi: 10.1002/art.38778 [published 
Online First: 2014/07/23]  
33. Huang J, Zhao L, Chen D. Growth factor signalling in osteoarthritis. Growth Factors 2018;36(5- 
6):187-95. doi: 10.1080/08977194.2018.1548444 [published Online First: 2019/01/10]  
34. Nijs J, Meeus M, Versijpt J, et al. Brain-derived neurotrophic factor as a driving force behind 
neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target?  
Expert Opin Ther Targets 2015;19(4):565-76. doi: 10.1517/14728222.2014.994506 
[published Online First: 2014/12/19]  
35. Pfizer. U.S. FDA Accepts Regulatory Submission for Tanezumab, a Potential First-in-Class 
Treatment for Patients with Chronic Pain Due to Moderate-to-Severe Osteoarthritis  [Available 
from: https://www.pfizer.com/news/press-release/press-
releasedetail/u_s_fda_accepts_regulatory_submission_for_tanezumab_a_potential_first_in_cl
as s_treatment_for_patients_with_chronic_pain_due_to_moderate_to_severe_osteoarthriti s 
accessed April 28 2021.  
36. Schnitzer TJ, Marks JA. A systematic review of the efficacy and general safety of antibodies to  
NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 2015;23 Suppl  
1:S8-17. doi: 10.1016/j.joca.2014.10.003 [published Online First: 2014/12/21]  
37. Shang X, Wang Z, Tao H. Mechanism and therapeutic effectiveness of nerve growth factor in 
osteoarthritis pain. Ther Clin Risk Manag 2017;13:951-56. doi: 10.2147/tcrm.S139814 
[published Online First: 2017/08/18]  
38. Coelho FG, Gobbi S, Andreatto CA, et al. Physical exercise modulates peripheral levels of 
brainderived neurotrophic factor (BDNF): a systematic review of experimental studies in the 
elderly. Arch Gerontol Geriatr 2013;56(1):10-5. doi: 10.1016/j.archger.2012.06.003 [published 
Online First: 2012/07/04]  
39. Gomes WF, Lacerda AC, Mendonça VA, et al. Effect of exercise on the plasma BDNF levels in 
elderly women with knee osteoarthritis. Rheumatol Int 2014;34(6):841-6. doi:  
10.1007/s00296-013-2786-0 [published Online First: 2013/06/07]  
40. Gold SM, Schulz KH, Hartmann S, et al. Basal serum levels and reactivity of nerve growth factor 
and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and 
controls. J Neuroimmunol 2003;138(1-2):99-105. doi: 10.1016/s0165-5728(03)001218 
[published Online First: 2003/05/14]  
41. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis 
Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. 
Arthritis &amp; rheumatology (Hoboken, NJ) 2020;72(2):220-33. doi: 10.1002/art.41142 
[published Online First: 2020/01/08]  
42. Fransen M, Crosbie J, Edmonds J. Reliability of gait measurements in people with osteoarthritis 
of the knee. Phys Ther 1997;77(9):944-53. [published Online First: 1997/09/18]  
43. Da Silva Santos R, Galdino G. Endogenous systems involved in exercise-induced analgesia. J 
Physiol Pharmacol 2018;69(1):3-13. doi: 10.26402/jpp.2018.1.01 [published Online First: 
2018/05/18]  
44. Galdino G, Romero T, Silva JF, et al. Acute resistance exercise induces antinociception by 
activation of the endocannabinoid system in rats. Anesth Analg 2014;119(3):702-15. doi:  
10.1213/ane.0000000000000340 [published Online First: 2014/07/01]  
45. Koltyn KF, Arbogast RW. Perception of pain after resistance exercise. Br J Sports Med  
1998;32(1):20-4. doi: 10.1136/bjsm.32.1.20 [published Online First: 1998/04/30]  

Page 13 of 14  
46. Esser S, Bailey A. Effects of exercise and physical activity on knee osteoarthritis. Curr Pain 
Headache Rep 2011;15(6):423-30. doi: 10.1007/s11916-011-0225-z [published Online First: 
2011/10/01]  
47. Ghasemi GA, Golkar A, Marandi SM. Effects of hata yoga on knee osteoarthritis. Int J Prev Med  
2013;4(Suppl 1):S133-8. [published Online First: 2013/05/30]  
48. Lauche R, Hunter DJ, Adams J, et al. Yoga for Osteoarthritis: a Systematic Review and 
Metaanalysis. Curr Rheumatol Rep 2019;21(9):47. doi: 10.1007/s11926-019-0846-5 [published 
Online First: 2019/07/25]  
49. Djalilova DM, Schulz PS, Berger AM, et al. Impact of Yoga on Inflammatory Biomarkers: A 
Systematic Review. Biol Res Nurs 2019;21(2):198-209. doi: 10.1177/1099800418820162 
[published Online First: 2018/12/24]  
50. Sivaramakrishnan D, Fitzsimons C, Kelly P, et al. The effects of yoga compared to active and 
inactive controls on physical function and health related quality of life in older adults- 
systematic review and meta-analysis of randomised controlled trials. Int J Behav Nutr Phys Act 
2019;16(1):33. doi: 10.1186/s12966-019-0789-2 [published Online First: 2019/04/07]  
51. Cramer H, Lauche R, Haller H, et al. Effects of yoga on cardiovascular disease risk factors: a 
systematic review and meta-analysis. Int J Cardiol 2014;173(2):170-83. doi:  
10.1016/j.ijcard.2014.02.017 [published Online First: 2014/03/19]  
52. Merighi A, Salio C, Ghirri A, et al. BDNF as a pain modulator. Prog Neurobiol 
2008;85(3):297317. doi: 10.1016/j.pneurobio.2008.04.004 [published Online First: 
2008/06/03]  
53. Obata K, Noguchi K. BDNF in sensory neurons and chronic pain. Neurosci Res 2006;55(1):1-10. 
doi: 10.1016/j.neures.2006.01.005 [published Online First: 2006/03/07]  
54. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors 2004;22(3):123- 
31. doi: 10.1080/08977190410001723308 [published Online First: 2004/11/03]  
55. Ritter AM, Lewin GR, Kremer NE, et al. Requirement for nerve growth factor in the 
development of myelinated nociceptors in vivo. Nature 1991;350(6318):500-2. doi:  
10.1038/350500a0 [published Online First: 1991/04/11]  
56. Snider WD. Functions of the neurotrophins during nervous system development: what the 
knockouts are teaching us. Cell 1994;77(5):627-38. doi: 10.1016/0092-8674(94)90048-5 
[published Online First: 1994/06/03]  
57. Woolf CJ, Safieh-Garabedian B, Ma QP, et al. Nerve growth factor contributes to the generation 
of inflammatory sensory hypersensitivity. Neuroscience 1994;62(2):327-31. doi: 10.1016/0306-
4522(94)90366-2 [published Online First: 1994/09/01]  
58. Nicol GD, Vasko MR. Unraveling the story of NGF-mediated sensitization of nociceptive sensory 
neurons: ON or OFF the Trks? Mol Interv 2007;7(1):26-41. doi: 10.1124/mi.7.1.6 [published 
Online First: 2007/03/07]  
59. McKelvey L, Shorten GD, O'Keeffe GW. Nerve growth factor-mediated regulation of pain 
signalling and proposed new intervention strategies in clinical pain management. J Neurochem 
2013;124(3):276-89. doi: 10.1111/jnc.12093 [published Online First:  
2012/11/20]  
60. Miller RE, Malfait AM, Block JA. Current status of nerve growth factor antibodies for the 
treatment of osteoarthritis pain. Clin Exp Rheumatol 2017;35 Suppl 107(5):85-87. [published 
Online First: 2017/10/03]  
61. Eldridge SM, Chan CL, Campbell MJ, et al. CONSORT 2010 statement: extension to randomised 
pilot and feasibility trials. BMJ 2016;355:i5239. doi: 10.1136/bmj.i5239 [published Online First: 
2016/10/26]  

Page 14 of 14  
62. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol 
items for clinical trials. Ann Intern Med 2013;158(3):200-7. doi: 10.7326/0003-4819-158-
3201302050-00583 [published Online First: 2013/01/09]  
63. Thabane L, Ma J, Chu R, et al. A tutorial on pilot studies: the what, why and how. BMC Medical 
Research Methodology 2010;10(1):1. doi: 10.1186/1471-2288-10-1  
64. Yarnitsky D, Bouhassira D, Drewes AM, et al. Recommendations on practice of conditioned pain 
modulation (CPM) testing. Eur J Pain 2015;19(6):805-6. doi: 10.1002/ejp.605 [published Online 
First: 2014/10/21]  
65. Lewis GN, Heales L, Rice DA, et al. Reliability of the conditioned pain modulation paradigm to 
assess endogenous inhibitory pain pathways. Pain research &amp; management  
2012;17(2):98-102. [published Online First: 2012/04/21]  
66. Rodriguez CS. Pain measurement in the elderly: a review. Pain Manag Nurs 2001;2(2):38-46. 
doi: 10.1053/jpmn.2001.23746 [published Online First: 2001/11/15]  
67. Jensen MP, McFarland CA. Increasing the reliability and validity of pain intensity measurement 
in chronic pain patients. Pain 1993;55(2):195-203. doi: 10.1016/0304-3959(93)90148-i 
[published Online First: 1993/11/01]  
68. Sullivan MJ, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. 
Psychological assessment 1995;7(4):524.  
69. Lorig KR, Sobel DS, Ritter PL, et al. Effect of a self-management program on patients with 
chronic disease. Eff Clin Pract 2001;4(6):256-62. [published Online First: 2002/01/05]  
70. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand  
1983;67(6):361-70. [published Online First: 1983/06/01]  
71. Smarr KL, Keefer AL. Measures of depression and depressive symptoms: Beck Depression 
Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric 
Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health 
Questionnaire-9 (PHQ-9). Arthritis Care Res (Hoboken) 2011;63 Suppl 11:S454-66. doi:  
10.1002/acr.20556 [published Online First: 2012/05/25]  
72. Roos EM, Roos HP, Lohmander LS, et al. Knee Injury and Osteoarthritis Outcome Score (KOOS)-
development of a self-administered outcome measure. J Orthop Sports Phys Ther  
1998;28(2):88-96. doi: 10.2519/jospt.1998.28.2.88 [published Online First: 1998/08/12]  
73. Collins NJ, Prinsen CA, Christensen R, et al. Knee Injury and Osteoarthritis Outcome Score  
(KOOS): systematic review and meta-analysis of measurement properties. Osteoarthritis 
Cartilage 2016;24(8):1317-29. doi: 10.1016/j.joca.2016.03.010 [published Online First: 
2016/03/26]  
74. Collins NJ, Misra D, Felson DT, et al. Measures of knee function: International Knee 
Documentation Committee (IKDC) Subjective Knee Evaluation Form, Knee Injury and  
Osteoarthritis Outcome Score (KOOS), Knee Injury and Osteoarthritis Outcome Score  
Physical Function Short Form (KOOS-PS), Knee Outcome Survey Activities of Daily Living 
Scale (KOS-ADL), Lysholm Knee Scoring Scale, Oxford Knee Score (OKS), Western Ontario 
and McMaster Universities Osteoarthritis Index (WOMAC), Activity Rating Scale (ARS), and 
Tegner Activity Score (TAS). Arthritis Care Res (Hoboken) 2011;63 Suppl 11:S208-28. doi:  
10.1002/acr.20632 [published Online First: 2012/05/25]  
75. Dobson F, Hinman RS, Roos EM, et al. OARSI recommended performance-based tests to assess 
physical function in people diagnosed with hip or knee osteoarthritis. Osteoarthritis Cartilage 
2013;21(8):1042-52. doi: 10.1016/j.joca.2013.05.002 [published Online First: 2013/05/18]