Knee Osteoarthritis Clinical Trial
Official title:
Pain Sensitization and the Risk of Poor Outcome Following Physiotherapy for Knee Osteoarthritis: A Protocol for a Prospective Cohort Study
Pain is the dominant symptom of knee osteoarthritis and recent evidence suggests factors
outside of local joint pathology, such as pain sensitization, can contribute significantly
to the pain experience. It is unknown how pain sensitization influences outcomes from
commonly employed interventions such as physiotherapy.
The aims of this study are, firstly to identify people with knee OA who display signs and
symptoms associated with pain sensitization using clinical tools and quantitative sensory
testing. Secondly, we will investigate if indications of pain sensitization at baseline are
associated with poor outcome following physiotherapy.
Methods and analysis:
This is a multi-centre prospective cohort study with 140 participants. Eligible patients
with moderate/severe symptomatic knee osteoarthritis will be identified at hospital
outpatient clinics. A baseline assessment will provide a comprehensive description of the
somatosensory characteristics of each participant by means of clinical examination,
quantitative sensory testing and validated questionnaires measuring pain and functional
capacity. Participants will then undergo physiotherapy treatment, in line with current
clinical guidelines. Follow-up post physiotherapy treatment (estimated to be at 3 months)
will assess pain, disability (sub-scales of Western Ontario and McMasters University Score
Osteoarthritis Index) and participants' global rating of change. These primary outcome
measures will dichotomise participants into treatment 'responders' and 'non-responders'
according to the Osteoarthritis Research Society International (OARSI) treatment responder
criteria.
For data analysis results from pressure pain thresholds, temporal summation and conditioned
pain modulation will create a composite score of pain sensitization. Logistic regression
will explore the relationship between response to physiotherapy and pain sensitization at
baseline while accounting for various cofounders.
BACKGROUND
The pathophysiology of knee OA pain is complex. Altered processing of nociceptive inputs at
spinal and higher brain centers may help explain discrepancies between pain severity and
pathological abnormalities in OA. Central sensitization is described as an increased
responsiveness of nociceptive neurons at spinal and supraspinal levels to normal or
sub-threshold afferent input leading to hyperalgesia. It may also include dysfunction of
endogenous pain control systems. Furthermore, peripheral pro-inflammatory mediators and
neuropeptides in knee OA can sensitize nociceptors, lowering their threshold for activation.
This increased responsiveness of peripheral nociceptors is referred to as peripheral
sensitization.
Both peripheral and central nervous system sensitization, clinically referred to as pain
sensitization can result can be an enhanced, persistent and more widespread pain response.
Recent studies have found the presence of increased pain sensitivity at remote sites,
enhanced temporal summation and hypersensitivity to various stimuli to be associated with
reports of more severe knee pain symptoms. These studies are cross-sectional and although
they link signs of sensitization with greater levels of pain and disability they cannot
infer causality.
There is some evidence to suggest increased pain sensitivity negatively affects treatment
outcomes. In painful musculoskeletal conditions such as shoulder impingement and lateral
epicondylalgia widespread pressure pain sensitivity and thermal hyperalgesia, have been
linked with a poorer prognosis. Surgical outcomes for knee osteoarthritis may also be
affected with the presence of increased pain sensitivity prior to total knee replacement
associated with more persistent pain after surgery.
Physiotherapy is a widely recommended conservative management approach. Studies of prognosis
in knee OA have focused on demographic and psychological variable, few studies have focused
on factors relating to abnormal pain processing. No longitudinal studies have explored
prognostic factors relating to pain sensitization and outcome following physiotherapy. In
whiplash associated disorders the presence of sensory hypersensitivity and cold hyperalgesia
has been shown to reduce the likelihood of a positive response to physiotherapy treatment.
Thus it is conceivable, but currently unproven, that knee OA patients with evidence of pain
sensitization have poorer outcomes following physiotherapy.
One obstacle to investigating the implications of pain sensitization is reliably identifying
it in the clinical setting. Clinical criteria proposed for assessing central sensitization
rely principally on the clinician's subjective interpretation of patient symptoms. Although
useful clinically, for research purposes more objective measures are preferable. Due to the
complexity of the pain experience it is inadvisable to rely on any single test to reflect
peripheral and central pain mechanisms. A multi-tissue assessment using a multi-modal
stimuli approach has been advocated, and will be adopted in this study. Recognised features
of central and peripheral sensitization previously identified in knee OA patients will be
incorporated into this study and these include extended areas of hyperalgesia, enhanced
temporal summation, and dysfunctional conditioned pain modulation.
This study will explore clinical outcomes of knee OA (pain, function, patient's global
assessment) following physiotherapy, investigating the association between key features of
pain sensitization and the likelihood of a poor outcome. Distinguishing patients at risk of
a poor outcome can help determine appropriate management strategies in a timely manner.
STUDY AIMS:
The main aims of the study are; firstly to provide a comprehensive description of the
somatosensory characteristics of people with pain associated with knee OA (by means of
clinical examination, QST, and validated questionnaires measuring pain, functional capacity
and quality of life) and secondly, to investigate if the presence of pain sensitization at
baseline is associated with poorer response to physiotherapy treatment.
METHODS AND ANALYSIS:
Study design:
A multi-centre observational cohort study with assessments at baseline, at 3 months (on
completion of physiotherapy treatment) and at six months will be conducted. Following the
baseline assessment for features of pain sensitization all participants will receive usual
physiotherapy care. The relationship between pain sensitization and outcomes in terms of
pain and disability will be explored through regression analysis.
Setting:
The study will be set in the physiotherapy outpatient departments of three large publicly
funded teaching hospitals in Dublin, Ireland.
Participants:
Patients with symptomatic knee OA referred for physiotherapy treatment by a hospital
consultant or clinical specialist physiotherapist will be eligible for inclusion.
Healthy controls:
Forty age and gender matched pain-free controls will be recruited. The controls will provide
reference data for QST results.
Recruitment procedure:
A consecutive sample of knee osteoarthritis patients with moderate/severe knee pain will be
recruited. Potentially eligible participants will be identified at musculoskeletal
assessment clinics and from physiotherapy outpatient waiting lists. A feasible recruitment
rate is estimated at 12 patients per month with recruitment continuing until the specified
numbers are achieved. Those who agree to participate will attend for a baseline assessment
prior to commencing physiotherapy treatment. Written informed consent will be obtained
before enrolment in the study.
Physiotherapy management:
Physiotherapy treatment will be in line with current clinical guidelines for the management
of knee OA. (McAlindon et al., 2014). A workshop led by the principal investigator will be
held at each recruitment site prior to study commencement where physiotherapists will
receive an update on clinical guidelines and current best evidence on management of knee OA.
This will standardise treatment to some degree, but intervention will be individualised at
the discretion of the treating physiotherapist.
Assessment
Baseline assessment:
Each baseline assessment will take approximately 50 minutes to complete at the physiotherapy
clinic by the principal investigator. Some questionnaires will be posted and completed in
advance by participants.
Follow up assessment:
The primary endpoint will be on completion of physiotherapy treatment (this is expected to
be at 3 months; estimated duration of a course of physiotherapy treatment).
Six months after enrolment into the study participants will complete a postal questionnaire
assessing pain and function. They will exit the study at this point.
Testing procedure:
In order to improve reliability of the assessment and minimise bias standardised assessment
procedures will be followed. Studies support the reliability of QST measures where protocols
are standardised and both the tester and participant are carefully instructed.
Outcome Variables:
Primary and secondary outcomes are outlined in section below.
Identifying and Quantifying Pain Sensitization:
Abnormal pain pressure thresholds and temporal summation have been previously used for
identifying sub-groups of patients with widespread pain hypersensitivity. Conditioned pain
modulation (CPM) is reflective of the endogenous inhibitory capacity of the nociceptive
system and dysfunction of CPM is associated with syndromes such as fibromyalgia and
temporomandibular joint disorder where central sensitization is a recognised hallmark. Pain
sensitization will therefore be operationalized by the presence of decreased PPTs and
enhanced temporal summation at local (knee) and remote (arm) sites in addition to
dysfunctional CPM. The cut-off point for what is abnormal or sensitized will be determined
when control data has been gathered and the spread or variability of 'normal' results is
seen. Points will be summed to produce a pain sensitization score where a higher score will
represent greater pain sensitization.
DATA ANALYSIS PLAN
Data will be analysed using SPSS v 20 (SPSS Inc., Chicago, IL). Descriptive statistics will
be calculated for all outcome measures at baseline.
Initial analyses will be exploratory to compare symptom profiles between people who respond
to treatment and treatment non-responders. Treatment responders will be categorised by the
OMERACT-OARSI responder criteria. Categorical variables will be analysed using chi-square
tests. Multivariate analysis of variance (MANOVA) will be used to compare continuous
normally distributed variables between responders and non-responders. The Kruskal-Wallis
test will be used for comparison of variables that are not normally distributed. A p value
of less than 0.05 will be considered significant.
A logistic regression model will be developed to predict response to physiotherapy treatment
with 'treatment responder' as the dependant variable. The model will be adjusted for
predetermined variables based on the previous literature (age, gender, obesity,
socioeconomic status, depressive symptoms, treatment adherence, comorbidities and presence
of widespread pain). The pain sensitization score will be entered into the regression model
as an independent variable.
Sample size:
The sample size was calculated based on the number of explanatory variables planned for
inclusion in the logistic regression model. It is intended to include 8 explanatory
variables and allow 15 participants for each explanatory variable. Recruiting 140
participants while allowing for a 20% loss to follow-up should ensure adequate numbers.
Dropouts:
All participants will be followed up on discharge from physiotherapy. Patients will be
considered lost to follow-up if they do not complete the primary outcome measure post
treatment.
DISCUSSION
To our knowledge this is the first study to examine the effects of pain sensitization on
clinical outcomes in response to physiotherapy in patients with knee OA.
There is a lack of a standardized protocol for assessing pain sensitization in the clinical
setting. This study selects tests based on their utility in the clinical setting. The
results may identify a small selection of outcome measures that are practical for assessing
pain sensitization and associated with an increased risk of poor outcome.
This clinically based observational study does not aim to investigate the effects of
specific physiotherapy treatments. It will observe people undergoing usual physiotherapy and
variation in the intervention is to be expected. Nonetheless an attempt to standardise care
to some degree will be made by using current evidence based guidelines and keeping a record
of the physiotherapy intervention and adherence for each participant.
Recruiting the participant sample from the secondary care setting will limit the
generalizability of study findings to patient populations in primary care.
Given its relatively short follow-up period we cannot infer causality directly from our data
with regard to pain sensitization and physiotherapy outcomes. Nonetheless it may point to a
relationship worthy of further investigation in order to better understand pain mechanisms
in knee OA and optimise physiotherapy outcomes in the future.
;
Observational Model: Cohort, Time Perspective: Prospective
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