Pain Informed Movement for People With Knee Osteoarthritis: A Pilot and Feasibility Randomized Controlled Trial
Phase: NA
Conditions: Knee Osteoarthritis
Sponsor: McMaster University

 
 
 
 
Title: Pain Informed Movement for People With Knee Osteoarthritis 
 
NCT Number: NCT06400329 
 
Date: April 3, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1. 
Introduction 
With an increasing global prevalence of knee OA (KOA) and no highly effective treatments 
for pain, there is an urgent need to improve conservative pain management strategies to 
avoid the associated negative outcomes such as limited mobility and multimorbidity [1]. 
Current clinical practice guidelines strongly recommend exercise and patient education as 
the core conservative management strategies [2,3]. Various types of exercises are 
recommended including neuromuscular exercises which are focused on improving knee 
functionality [4]. However, these treatments are only moderately effective for controlling 
pain [5], which therefore begs for a deeper understanding of the mechanisms of KOA pain 
and filling the corresponding gaps with mechanism-based treatment strategies. 
Current recommended methods for conservative management are not predicated on pain 
mechanisms, while evidence for neural sensitization and dysregulation of intrinsic pain 
modulation is widely reported [6]. Mind-body approaches have the potential to fill these 
gaps in the management of KOA through a combination of physical postures, breathing 
techniques, meditation, mindfulness, and relaxation [7]. The effects are reported to be 
mechanistically related to the regulation of nociceptive signals [8]. For instance, breathing 
exercises can lead to the disruption of the association of pain and sympathetic nervous 
system activation [9], leading to modulation of autonomic functions [10]. Meditation and 
relaxation can create a state of calm and provide a sensation of being in a place of safety (a 
parasympathetic state) [11], which can lead to changes in one's pain experience [12]. 
Mindfulness and mindful movements can improve where and how to focus, develop skills 
to control the response to pain [13], and influence the pain experience through emotional 
regulation and interoception [8]. 
A management strategy that can be a valuable addition to exercise, 
Pain Neuroscience Education (PNE) is a technique that shifts the focus from the diseased 
knee joint and the assumption that pain stems from degenerative structural changes [14]. 
Unlike standard OA education that has historically had a biomedical influence [14], PNE 
reconceptualizes pain as a danger signal and introduces intrinsic modulation of pain to 
influence the pain experience. Omitting biomedical language from KOA education can lead 
to significantly lower perceptions that physical activity is injurious to the knee joint, lower 
fear of movement, and improve participation in exercise [14]. Combined with active 
treatment strategies such as exercise, PNE results in positive changes in pain [15]. 
The need for high quality research that evaluates the effects of mind- body approaches in 
managing KOA pain and understanding how they may modify altered nervous system 
processing is needed. Our group has developed a program we call Pain Informed 

Movement, which is a combination of neuromuscular exercise, mind-body techniques, and 
PNE with the aim of improving intrinsic pain modulation in people with KOA. Although each 
of these components as a standalone technique can improve pain in KOA, their cumulative 
effect may be more substantial and has the potential to lead to an enhancement of 
outcomes, as each component can lead to optimization of the other. Given that the 
feasibility and acceptability of the Pain Informed Movement program has been previously 
established [16], further evaluation of this program compared to standard care is 
warranted. This paper presents a detailed protocol for a pilot randomized controlled trial 
(RCT) to collect pilot data, as well as initial efficacy data on the comparison of Pain 
Informed Movement program with neuromuscular exercise and standard OA education in 
people with KOA. This study has been approved by the Hamilton Integrated Research 
Ethics Board and registered on clinicalt rials.gov (ID: NCT05730829). 
1.1. 
Study objectives and hypothesis 
The objectives of this study are 1) to pilot test the procedures of this RCT and investigate 
the feasibility with the primary outcome of rate of follow-up, 2) assess secondary aspects 
of feasibility such as acceptability of the programs, rates of recruitment, adherence, 
compliance, as well as burden and adverse events) and 3) explore effects of Pain Informed 
Movement program on subjective and objective measures of KOA pain when compared to a 
usual conservative management strategy for people with KOA. Given the additional and 
improved components of the Pain Informed Movement program and it's feasibility 
established in the previous phase [16], we hypothesize that this pilot RCT will show 
feasibility of comparing the two treatment strategies, and the Pain Informed Movement 
program will show promising results. 
 
2. 
Methods 
2.1. 
Study design 
This is a pilot study with a nested qualitative component designed as a parallel, 
randomized, single-centre, two-arm clinical trial with a 1:1 allocation ratio. Informed 
consent will be obtained from all participants prior to initiating the study. All participants 
will be invited to complete an exit survey and take part in focus group interviews at program 
completion. Fig. 1 depicts the trial design. The procedures will be followed in accordance 
with the ethical standards of the responsible committee on human experimentation 
(institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. 
The Conceptual Framework for Defining Feasibility [17] and Pilot studies and the Standard 
Protocol Items: Recommendations for Intervention Trials will be used [18]. Following 

program completion, the study results will be re- ported using the extended CONSORT 
guideline for pilot trials as well as the TiDIER guidelines [17,19]. The study protocol is 
registered at clinic altrials.gov #NCT05730829. 
2.2. 
Study participants 
Sample size is based on the primary outcome of complete follow-up using the confidence 
interval method for calculating sample size in pilot trials [20]. We will aim for 90% follow-up 
but will consider the trial successful if we achieve 81%. To achieve a margin of error of 9%, 
with 10% added for attrition, we will require 66 participants (n ¼ 33 per arm). 
Participants will be recruited through the email lists of the McMaster University's 
community and research centers and their social media pages. Additionally, the study 
poster will be placed on other social media channels (e.g., Twitter, Facebook 
advertisements) and flyers will be placed in local Orthopaedic surgeon, Rheumatologist, 
and Physiatrists offices. 
The inclusion and exclusion criteria are listed in Table 1. 

 
2.3. 
Screening and assessments 
Potential participants will contact the research team through the contact information 
provided in the flyer and study poster. Screening will be conducted over the telephone and 
study information will be provided. Consenting and eligible participants will be a sent an 
individualized link to the written consent form, written study information, and baseline 

questionnaires. Those who pass the screening, including exercise safety, will be invited to 
an in-person physical assessment. Upon program completion, participants will be sent the 
questionnaires again (which also include the exit survey questions) and will attend a 
second in-person assessment of physical measures. Focus groups will be conducted to 
further assess the participants’ perception of the study. If a participant has bilateral KOA, 
the most symptomatic knee will be studied. If both knees are equally affected, the 
dominant knee will be studied, which is the knee with which the individual steps first when 
initiating gait. 
2.4. 
Randomization and blinding 
Participants will be randomized with an allocation ratio of 1:1 into one of two treatment 
groups (Pain Informed Movement or neuromuscular exercise and standard OA education) 
using a REDCap randomization module. The process of randomization will be conducted by 
a member of the research team who is independent of the recruitment process. 
Additionally, the assessors responsible for conducting baseline and follow-up 
assessments will be blinded and not involved in recruitment. Blinding of exercise 
instructors is generally not possible in studies of physical interventions (e.g., exercise) [21]. 
Participants will be blinded to study hypotheses and the two treatment groups. As both 
arms of the study are providing exercise-based interventions and education, participants 
will be provided limited details of each intervention arm so as to blind them from knowing 
which is the intervention and which is the control. This will help minimize any bias that 
occurs by knowledge of group assignment and perception of treatment effects. 

 
 
2.5. 
Interventions 
The intervention will start within two days of the physical assessments with participants 
receiving educational videos approximately 10–14 days before the first exercise session. 
2.5.1. Pain Informed Movement program 
Participants in this group will receive an 8 week in-person group exercise program held 
twice weekly, in which they will receive exercise instructions and PNE. They will also be 

asked to complete a third exercise session at home weekly. Participants will be provided 
with tracking sheets to note their compliance and progress. 
The PNE component will consist of several short videos that are provided online for the first 
five weeks of the program (the videos are divided into short segments, each with a separate 
subject, totaling 20–30 min/week)). The videos will provide simple explanations of 
nociception processing by the nervous system, how it can be modulated through 
upregulation or downregulation of signals to increase or decrease pain and that pain does 
not accurately signify the extent of tissue damage, particularly when experiencing chronic 
pain. The videos will also offer techniques to reconceptualize pain and movement not as 
imminently dangerous. In addition, the videos will introduce and provide a demonstration 
of mind-body techniques that will be provided progressively each week. The mind-body 
techniques will include breath awareness and regulation, body awareness and muscle 
tension regulation, and aware- ness of pain related thoughts and emotions. The techniques 
will then be implemented in the in-person exercise sessions where participants are asked 
to incorporate them into the their performance of the exercises. Instructions will be 
provided on how to ‘nudge the edge’ of pain which is conceptualized as a balance between 
challenging current physical abilities during the exercises and being successful at not 
leaving pain provoked and/or function limited after exercise. Participants will be instructed 
to use breath, body tension, thoughts, and emotions as guideposts to their pain in order to 
successfully nudge its edge. Participants will be given the opportunity to ask questions 
during the in-person sessions. 
The exercise component (75 min) will consist of three parts (in sequence): 
Part one: the first part is the warm-up which begins with a centering practice aimed at 
regulating physiology. Next, warming movements of the shoulders, legs, and spine will be 
instructed. 
Part two: of the second part is the main exercises (based on the original NEMEX-training 
program [4]  This part is divided into four sections: core stability, postural orientation, lower 
extremity muscle strength, and functional exercises with an emphasis on proper alignment 
of the knee over the foot. Within each section, there are two types of exercises and three 
levels for progression. Participants will be instructed to complete each exercise for two to 
three sets of eight to 15 repetitions. For the core stability section, one exercise is instructed 
based on breaths. When an exercise is performed with good quality of the performance, 
with minimal exertion, and with control of the movement, it can be progressed by 
increasing repetitions or the load (going through the levels). The exercises will be 
performed with both the affected and the unaffected leg. 

Part three: the third and last part is cooldown which consists of the same warmup 
movements plus relaxation and guided self-reflection. Participants will be cued to use the 
PNE concepts and mind-body techniques during the exercise sessions. 
Participants will also complete a third home session (weekly) which is facilitated by 
handout sheets. The exercise component will be delivered by an experienced yoga teacher 
with training in the integration of pain science and mindful movement. 
2.5.2. Neuromuscular exercise and standard OA education 
Participants in this group will receive an 8-week in-person group exercise program held 
twice weekly, in which they will receive exercise instructions and standard OA education. 
Participants will be provided with tracking sheets to note their compliance and progress. 
The exercise component (60 min) of this group will be similar to that of the other group 
without the added mind-body techniques. Similarly, a third home session (weekly) will be 
facilitated by exercise handout sheets. The exercise instructions will be delivered by a 
physiotherapist. The standard OA education will consist of several short videos (20–30 
min/week for the first two weeks provided through online videos) and will cover the 
following topics: pathophysiology of OA, common OA symptoms, risk factors, the effects of 
exercise, and self- management tips. Participants will be given the opportunity to ask 
questions during the in-person sessions. 
2.6. 
Safety 
Participants will be provided with a tracking sheet to note any adverse events (AEs) 
throughout the study. The instructors will also monitor for adverse events during the in-
person sessions. If any AE happens, participants will be instructed to tell the instructor to 
modify the exercises or reduce the intensity if necessary. AEs will be defined as any 
problem that lasts for >2 days and/or causes the participant to seek other treatment. 
2.7. 
Primary and feasibility outcomes 
The primary outcome measure is the follow-up rate (i.e., number of participants that 
completed the program and attended follow-up). Other feasibility outcomes include: 
acceptability (content, format, frequency, and duration) of the Pain Informed Movement 
program compared to the control group, recruitment rate, burden of procedures, 
adherence rate (i.e., number of participants that attended all in-person sessions), 
compliance to the program (i.e., number of participants that reported completion of at 
least three exercise sessions per week), and AEs. A priori success criteria will be used to 
determine feasibility and acceptability of the programs (Table 2). 
 

Table 2:  
 
 
2.8. 
Secondary outcomes and descriptive data 

Participant characteristics such as age, sex, gender, education, marital status, race, 
number of people in household, height, and weight will be collected. A list of secondary 
outcomes is provided in Table 3. 
Table 3: Secondary outcomes. 
Outcome 
Tool 
Description 
Comorbidities 
Modified Charlson 
Comorbidity Index 
(CCI) 
Assessed the presence of 19 comorbidities in 
participants. The CCI has been used in many 
patient populations, including knee osteoarthritis 
(KOA). 30  
Central 
sensitization  
Mechanical 
Temporal 
Summation (TS) 
A 512mN weighted probe was applied at the volar 
wrist opposite to the index knee. Participants 
were asked to rate their pain between 0 and 100 
31. Then, the same stimulus was applied 10 times 
at the rate of 1/second (guided by a metronome), 
and participants asked again to rate their pain. TS 
was defined as present when, compared with the 
initial trial, the participant reported increased 
pain following the second trial. 31 The validity of 
mechanical TS has been reported in people with 
KOA. 31  
Endogenous 
pain 
modulation 
Conditioned Pain 
Modulation (CPM) 
CPM was assessed in the following steps 32:  
1) at the proximal anterior shin on the unaffected 
knee, an ascending measure of pressure pain 
threshold (PPT) was evaluated;  
2) at the opposite volar forearm, a conditioning 
stimulus in the form of forearm ischemia was 
applied using a blood pressure cuff and squeezing 
a stress ball until a pain rating of 4/10 was 
reached;  

3) PPT at the anterior shin was repeated with the 
cuff remaining inflated. 32  
4) an index was created by calculating the percent 
efficiency of CPM (%CPM) as PPT2/PPT1, 
multiplied by 100; whereby %CPM ≤ 100 indicated 
inefficient pain modulation 33. CPM testing has 
demonstrated good intra-session reliability 34. 
Pain intensity 
Numeric Rating 
Scale  
Average pain intensity in the past 24 hours, past 
week, and worst pain in the past 24 hours was 
recorded. Questions were rated on an 11-point 
scale where participants selected a rating 
between 0-10, with zero representing ‘no pain’ and 
10 representing the ‘worst imaginable pain. 35. The 
Numeric Rating Scale is reported to have 
excellent inter-rater reliability and acceptable 
validity in people with KOA 36. 
Pain 
catastrophizing  
Pain 
Catastrophizing 
Scale (PCS) 
The PCS 37 is a 13-item self-reporting instrument 
for catastrophizing in the context of actual or 
anticipated pain, with higher scores indicating 
higher pain catastrophizing. The validity of the 
PCS for measuring pain catastrophizing in people 
with KOA has been reported 38. 
Chronic pain 
self-efficacy  
Self-Efficacy for 
Managing Chronic 
Disease 6-item 
scale (SEMCD-6) 
Higher reported scores on the SEMCD-6 indicate 
higher self-efficacy 39. The SEMCD-6 has high 
internal consistency with significant correlations 
with other health outcomes 40. 
Anxiety and 
depressive 
symptoms 
Hospital Anxiety 
and Depression 
Scale (HADS) 
Higher scores on the HADS 41 indicate increased 
severity of anxiety and depression symptoms. The 
HADS is a brief and reliable measure of emotional 

distress in general in chronic populations 42. 
Validity and reliability of the HADS have been 
previously established 42. 
Fear of 
movement 
Brief Fear of 
Movement Scale 
for Osteoarthritis 
(BFMSO) 
The BFMSO has 6 items that are derived from the 
Tampa Scale for Kinesiophobia (TSK) and uses a 
4-point Likert scale with higher values indicating 
higher levels of kinesiophobia 43. The BFMSO has 
been reported to have adequate validity 43. 
Knee injury and 
outcomes 
Knee Injury and 
Osteoarthritis 
Outcome Score 
(KOOS) 
The KOOS pain and function in daily living and 
QoL subscales were used to assess self-reported 
opinions about patients’ knee and associated 
problems. Scores ranged from 0-100 with zero 
representing extreme knee problems and 100 
representing no knee problems 44. KOOS has 
adequate internal consistency and validity in 
people with KOA 45.  
Type of KOA 
pain 
Intermittent and 
Constant 
Osteoarthritis Pain 
(ICOAP) 
The ICOAP knee version was used to assess the 
different types of knee pain experienced by 
participants 46. The ICOAP knee version has two 
sections: 1) ‘constant pain’ has 5 items that asks 
about pain that is present all the time, and 2) the 
‘intermittent pain’ has 6 items that asks about 
pain that comes and goes. The psychometric 
properties of the ICOAP such as reliability and 
validity have been previously established 47. 
Other painful 
body parts 
Body diagram 
Participants were asked to indicate any other 
areas where they experience pain (e.g., neck, 
shoulders, back) on a body diagram. Body 

diagrams have shown to be a reliable method for 
indication of painful body parts 48. 
Functional leg 
strength  
30 second sit-to-
stand test 
The 30 Second Sit to Stand Test was used as a 
performance test 49. The maximum number of 
chair stand repetitions completed during a 30 
second interval was noted. A standard chair 
height was used. The 30 Second Sit to Stand Test 
has been reported to be a reliable measure of 
functional leg strength and endurance 49. 
Brain derived 
neurotrophic 
factor (BDNF) 
and nerve 
growth factor 
(NGF) 
Blood analysis 
(blood draws 
under fasting 
conditions) 
Altered levels of BDNF are involved in the 
pathophysiology of chronic pain 50. NGF has been 
shown to be elevated in a wide variety of chronic 
pain conditions including KOA 51. Five ml of blood 
was drawn for analysis of BDNF and NGF and 
samples were centrifuged at 4 degrees Celsius for 
10 minutes at 1000g. Collected serum was stored 
at -80˚C. Serum levels of BDNF, diluted 1:100, 
were measured using Biosensis 
Human/Mouse/Rat BDNF ELISA kits read on a 
Spectramax i3 spectrophotometer. Serum levels 
of NGF were measured in duplicate, after diluting 
2X in Reagent Diluent, with R&D Systems Human 
beta-NGF DuoSet ELISA kits read on a Multiskan 
Go spectrophotometer.  
Medication use  Survey question 
Participants were asked to indicate any 
medication that they take on a regular schedule 
including prescription medications, non-
prescription, over the counter, vitamins, herbal, 
and alternative medicines.  

Perspective on 
knee 
replacement 
surgery 
Survey question 
Three questions were asked: 1. Are your knee 
symptoms so severe that you wish to undergo 
knee replacement surgery? 51 2. Do you think knee 
replacement surgery is eventually inevitable? 52 3. 
In your opinion, what factor(s) can lead to better 
outcomes after knee replacement surgery?  
Perspectives 
on 
effectiveness 
of components 
of intervention 
Survey question 
Participants were asked to rank the effectiveness 
of the intervention components for pain 
management that they received. i.e. mind-body 
techniques, pain neuroscience education and 
strengthening exercises vs OA education and 
strengthening exercises. 
 
2.9. 
Exit survey and focus group 
At follow-up, a satisfaction survey will be conducted. Participants who indicated upon 
initially consenting to the study that they would like to participate in a focus group will be 
contacted. Qualitative description will be used to explore participants’ experience and 
perceptions of the feasibility and acceptability of the Pain Informed Movement program as 
well as the standard treatment as well as the procedure for the entire study. An interview 
guide developed by patients and practitioners will be used. The focus groups will be 
conducted virtually consisting of six to eight participants and will last about 60–90 min. The 
session will be recorded, and transcripts will be produced to ensure accuracy of the 
responses. 
2.10. Data integrity 
The health information collected in this study will be kept confidential on a secure REDCap 
platform maintained by McMaster University. To ensure confidentiality, each participant 
will be given a unique identification number. At the end of the study, the anonymized data 
will be kept and will comprise a resource database. The researchers and the ethics board 
may access the study records to monitor the research and verify the accuracy of study 
information. No records with identifying information will be allowed to leave the principle 
investigator's office. Study information will be kept for 10 years, then will be permanently 
destroyed. 

 
2.11. Analysis 
Descriptive statistics will be used to report feasibility outcomes. The quantitative analysis 
of secondary outcomes will be by intention- 
to-treat principles. Repeated measures analysis of variance (ANOVA) will be used to assess 
the amount of change in outcome measures and compare them between the two groups 
using means and 95% CIs. Similarly, within group differences will be analyzed using the 
paired sample's t-test and will be reported using means and 95% CIs. Where possible we 
will also report minimally important difference. 
The transcripts of the focus group interviews will be analyzed using thematic content 
analysis to identify suggestions for program modification [46]. Line-by-line reading of the 
transcripts will be performed and thematic patterns will be explored. Once themes and 
patterns are identified, each meaningful segment of text will be assigned a conceptual 
code. 
 
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