Adults with patellofemoral pain do not exhibit manifestations of peripheral and central sensitization when compared to healthy pain-free age and sex matched controls – An assessor blinded cross-sectional study
Adults with patellofemoral pain do not exhibit manifestations of peripheral and central sensitization when compared to healthy pain- free age and sex matched controls ± An assessor blinded cross-sectional study
Michael Skovdal Rathleff 0 1
Camilla Rams Rathleff 1
Aoife Stephenson 1
Rebecca Mellor 1
Mark Matthews 1
Kay Crossley 1
Bill Vicenzino 1
0 Research Unit for General Practice in Aalborg, Department of Clinical Medicine at Aalborg University, Aalborg University , Aalborg , Denmark , 2 Orthopaedic Surgery Research Unit, Aalborg University Hospital , Aalborg , Denmark , 3 University of Queensland, School of Health and Rehabilitation Sciences: Physiotherapy , Brisbane , Australia , 4 College of Science, Health and Engineering. La Trobe University , Bundoora , Australia
1 Editor: Qinhong Zhang, Stanford University School of Medicine , UNITED STATES
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The author(s) received no specific
funding for this work
Competing interests: The authors have declared
that no competing interests exist
Patellofemoral Pain (PFP) is highly prevalent among adults and adolescents. Localized
mechanical hyperalgesia around the knee and tibialis anterior have been observed in people
with PFP, but limited knowledge of potential manifestations of central sensitisation exists.
The aims of this study were to study conditioned pain modulation (CPM) and wide-spread
hyperalgesia in adults with PFP. This assessor-blinded cross-sectional study design
compared CPM and mechanical pressure pain thresholds (PPT) between 33 adults (23 females)
diagnosed with PFP and 32 age and sex matched pain-free controls. The investigator taking
the PPT measurements was blinded to which participants had PFP. PPTs were reliably
measured using a Somedic hand-held pressure algometer at three sites: 1) The centre of
the patella, 2) the tibialis anterior muscle and 3) a remote site on the lateral epicondyle. For
the assessment of CPM, experimental pain was induced to the contralateral hand by
immersion into a cold water bath (conditioning stimulus), and assessment of PPTs (the test
stimulus) was performed before and immediately after the conditioning stimulation. On average,
the CPM paradigm induced a significant increase in PPTs across the three sites (6.3±
13.5%, P<0.05), however there was no difference in CPM between young adults with PFP
compared to the control group, (F(1,189) = 0.39, P = 0.89). There was no difference in
mechanical PPTs between the two groups (F(1,189) = 0.03, P = 0.86). Contrary to our
a-priori hypothesis, we found no difference in CPM or PPT between young adults with PFP and
age and sex matched pain-free controls.
One of the most long-lasting and troublesome knee conditions among adolescents and adults
is patellofemoral pain (PFP). Patellofemoral pain is a clinical diagnosis of pain felt anteriorly
around the patella, which increases during prolonged sitting, squatting, kneeling and stair
]. The prevalence of PFP among adolescents and young adults is 7% and 9%
respectively [2±4] and may account for up to 17% of all knee related problems seen in primary care
Patellofemoral pain is often considered a `diagnosis of exclusion', in the prescence of
anterior knee pain with no other diagnosable pathology [
]. As such, the underlying
aetiology is largely unknown, although it is often considered a loading related condition [
This is because PFP often presents in highly active populations such as runners and
military recruits, and has been associated with altered knee joint loading [
]. Despite this,
patellofemoral pain also presents in inactive adolescents [
], and the patterns of pain are
often diffuse and highly variable [
], and can persist even when adolescents modify or
reduce physical activity [
], which undermines the notion that it is primarily driven by
load. Additionally, Boudreau et al. noted that a longer symptom duration was associated
with a greater distribution or spreading of the area of pain [
]. Together, these observation
have led recent studies to investigate the role of other potential contributors to the pain
experience, including psychological factors [
] and pain sensitivity [
]. Studies of pain
sensitivity have demonstrated local mechanical hyperalgesia around the patella in
] and adult females with PFP [
], while widespread mechanical hyperalgesia has
only been reported in young female adults [
Other adaptive characteristics of the pain system such as pro-nociceptive (e.g. temporal
summation of pain) and anti-nociceptive (e.g. conditioning pain modulation)
mechanisms have also been assessed in individuals with PFP [
]. Conditioned pain modulation
(CPM) is an anti-nociceptive mechanism, which is representative of descending control of
pain in the central nervous system. It is thought to occur through diffuse noxious
inhibitory control (DNIC) which modulates pain processing at the spinal cord level [
used proxy of the effectiveness of the endogenous analgesic system and is evident in
longstanding pain conditions such as knee and hip osteoarthritis [16±18], where it is
associated with development of post-operative pain, in addition to other non-arthritic chronic
pain conditions [
]. Interestingly, one study previously identified impared
conditioned pain modulation in young females with PFP, but no differences in pro-nociceptive
mechanisms (temporal summation) . Little is known about CPM in young adults with
The primary aims of this study were to compare (i) CPM, and (ii) wide-spread hyperalgesia
in young adults with PFP to an age and sex matched pain-free control group. We hypothesised
that young adults with PFP would have an impaired CPM compared to pain-free controls, and
that PPTs around the patella and at sites remote from the area of self-reported knee pain
would be lower among young adults with PFP.
This cross-sectional study compared PPT and CPM in young adults diagnosed with PFP to a
sex and age-matched comparison group of healthy pain-free controls. The study was approved
by the local ethics committee at the University of Queensland, Brisbane, Australia and all
participants provided written informed consent. The reporting of the study complies with the
`Strengthening the Reporting of Observational studies in Epidemiology' (STROBE) statement
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Participants with PFP were recruited from the University of Queensland campus through
advertisements in University News, flyers and verbal information to lecture attendees and
from newspaper advertisements in the greater Brisbane area. Participants underwent a short
telephone screening to determine eligibility. If participants had anterior knee pain with an
insidious onset of more than six weeks they were invited to attend a clinical examination by an
experienced, registered physiotherapist. We used similar inclusion and exclusion criteria as
Collins et al [
] which aligns with current recommendations [
]. During the clinical
examination, individuals were diagnosed with PFP if they met the following criteria: insidious onset
and a duration of anterior knee or retro-patellar pain for at least the past six weeks; pain
provoked by at least two of the following knee loading activities: squatting, running, hopping, or
stair walking and ability to read/understand English. Exclusion criteria were concomitant
injury or pain from other body sites, or other knee structures; previous knee surgery;
patellofemoral instability; knee joint effusion; use of physiotherapy for knee pain within the previous
six months; currently undergoing medical treatment for their knee pain; known neurological
or medical conditions.
Healthy pain-free controls who were matched for age and sex were recruited from the same
population setting. In addition, participants diagnosed with PFP were asked to invite a friend
with no knee pain to participate. The inclusion criteria for pain-free controls were: no current
self-reported musculoskeletal pain; no self-reported prior surgery in the lower extremity; no
self-reported neurological or other medical conditions.
The a-priori defined primary outcome was the percentage change in mechanical PPT from
before application of a conditioning stimulus to immediately after. Secondary outcomes
included the baseline assessment of mechanical PPT at the three test sites before the
All mechanical PPT measurements were performed by a female investigator blinded to
whether participants were diagnosed with PFP or were pain-free controls. The measurements
were collected from the most painful knee and shin and contra-lateral elbow. All participants
were asked to refrain from strenuous exercise and avoid taking pain medication for 48 hours
prior to assessment. Mechanical PPTs were measured with a hand-held pressure algometer
(Algometer Type II; Somedic AB, Sweden). Identical to a previous study [
], we measured
mechanical PPTs at one site on the centre of the patella, one site on the tibialis anterior
(defined as the muscle belly of the tibialis anterior 5 cm distal to the tibial tuberosity) and a
control (remote) point on the lateral epicondyle of the humerus. The probe of the mechanical
algometer was 1cm2, and placed perpendicular to the skin during the PPT measurements.
Pressure was applied at a rate of 30 kPa/s and participants were instructed to indicate when the
sensation changed from a sensation of pressure to the first onset of pain. Measurements were
done with the participants resting in a reclining position and the knee flexed to approximately
60 degrees. Mechanical PPTs was measured twice at each site and the average was used for
For the assessment of CPM, a painful conditioning stimulus was applied to the hand, con
tralateral to the most painful knee, by immersion into a cold water bath. The test stimulus
consisted of PPTs tested prior to, and immediately after the conditioning stimulus. The CPM was
defined as the percentage change in PPTs (test stimulus) from before to immediately after the
conditioning stimulation. The conditioning stimulation was induced by immersion of the
hand into a cold water bath (12 degrees, non circulating) for two minutes. Based on pilot
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testing, we expected this conditioning stimulus to cause the participant to report at least 4±6
out of 10 on a Numeric Rating Scale (NRS) of pain. Just before removing the hand from the
water, the participant was asked to rate their pain intensity on a 0±10 NRS, with 0 defined as
ªno painº and 10 as ªworst pain imaginableº.
Self-reported pain and disability
In addition to PPTs, the following clinical self-reported measures were collected from the
group with PFP by the person doing the physical assessment of eligibility: 1) Knee Injury and
Osteoarthritis Outcome Score (KOOS) with scores ranging from 0 (worst) to 100 (best) and
covers the five domains: pain, symptoms, function in daily living, function in sport and
recreation, and knee-related quality of life; 2) Kujala is a frequently used validated outcome measure
for patients with PFF [
] where a maximum score of 100 represents fully functional and
lower scores indicate greater pain and/or disability; 3) Numerical Rating Scale (NRS) for worst
pain intensity during the last week; 4) symptom duration (months); 5) most painful knee
(right/left); 6) uni- or bilateral pain (yes/no) and the pain localisation.
A modified version of The Knee Pain Map (KPM) was used to describe pain location and pain
]. The KPM is an interviewer-administered survey that instructs patients to
point to the area of pain. The participant sat on an examination table with knees flexed over
the edge of the table, and pointed at or covered the area or areas that hurt with the fingers or
hand. The interviewer recorded the areas of pain on the knee diagram (map). Following the
survey, the same assessor interpreted all the drawings. Based on the drawings, pain localisation
was classified as retropatellar (on the patella), peripatellar, or a combination of both
retropatellar and peripatellar. In addition, if the pain extended over a region two fingers width in size or
smaller, it was defined as localised knee pain. If the pain covered an area more than two but
less than four fingers width in size, it was defined as regional knee pain. If the participant felt
the pain was spread over an area larger than this or said that they felt the pain all around and
on the patella, the pain was defined as diffuse knee pain. If participants with PFP reported
more than four local areas of pain or more than two regions of pain in the knee, the pain was
classified as diffuse.
Before collecting data for the study, seven participants (two with PFP and five healthy) partici
pated in an intra-day and intra-tester test-retest reliability study. There was one hour between
each test. The reliability of PPT measures for each of the three sites were >0.98 (ICC 3.1,
twoway mixed agreement model) and the reliability of the change in PPT after the conditioning
stimulation was >0.85 (ICC 3.1, two-way mixed agreement model) for all three sites.
The sample size was calculated based on a difference between groups of 50 kPa in a change on
the primary outcome of PPT around the knee after the conditioning stimulus (corresponding
to a 50 kPa change in pain-free and 0 kPa change among individuals with PFP). The common
standard deviation was estimated to be 75 kPa. Using a power of 0.80 and alpha at 0.05 this
corresponds to a sample size of 35 in each group.
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The primary analysis was a comparison between groups in the mean percentage change in
PPT at the three test sites after the conditioning stimulation was applied. Secondary analysis
included a comparison of PPT at each of the three sites between groups.
A two-way ANOVA was used with group (PFP, controls) and test site (patella, tibialis ante
rior, lateral epicondyle) as factors to test the difference between groups in CPM and PPTs.
This analysis was also conducted as an ANCOVA with sex as a covariate. All calculations were
performed using Stata version 11 (StataCorp, College Station, Texas, USA). Mean values ±SD
are reported if data are normally distributed. If data are non-normally distributed they are
presented as median and interquartile range (IQR).
The adults with PFP (n = 33) had a median symptom duration of 24 months (Table 1). The
knee pain map showed that most participants with PFP reported retropatellar pain (n = 18) or
combined peripatellar and retropatellar pain (n = 12), with only one reporting peripatellar
pain. Thirty adults with PFP participated at least weekly in recreational sporting activities
above 30 minutes with 22 reporting a decrease in sports participation after they developed
knee pain. The KOOS subscale scores were: KOOS-pain (75±12), KOOS-symptoms (83±10),
function in daily living (86±11), function in sport and recreation (60±20) and knee-related
quality of life (QoL) (51±20) and the Kujala score was 76±8.
The CPM testing induced a significant increase in PTTs across the three sites (mean CPM
range: 6.3±13.5%, P<0.05), but there was no difference in CPM between the PFP and control
groups, (F(1,189) = 0.39, P = 0.89, Fig 1, mean values presented in S1 File) nor when adjusting
for sex using an ANCOVA. There was no difference in mechanical PPTs between the two
groups (F(1,189) = 0.03, P = 0.86), Fig 2, mean values presented in S1 File). There was a mean
increase in pain NRS of 7 (IQR: 6±8) after the hand was immersed into cold water (the
Patellofemoral pain (n = 33)
Pain-free controls (n = 32)
Fig 1. Percentage change in PPTs after the conditioning stimulus across the three test sites (individual patient data and group mean).
Explorative analyses within the PFP group
An explorative analysis (not pre-defined) of the association between PPT and self-reported measures of KOOS QoL, KOOS pain, worst pain intensity in the previous week, and symptom duration, revealed no significant or relevant associations (spearman rank correlation<0.31, P>0.08).
After a median split of symptom duration (at 24 months) into short and long duration, and
worst pain intensity (at 5 NRS) into low and high intensity pain, in order to create four distinct
subgroups, there were clear patterns towards lower PPTs among the two groups of patients
with the highest pain intensity (Figs 3 & 4). As these groups were very small, no formal
hypothesis testing was done and this should only be considered explorative to inform future studies.
Contrary to our hypotheses, we found no difference in CPM or PPT at the knee, tibia and elbow between adults with PFP and age and sex matched pain-free controls. Collectively, these results suggest that this group of patients with PFP does not have altered peripheral or central processing of pain compared to age and sex matched pain-free controls.
Explanation of results
The participants in this study all experienced knee pain during activities that load the patellofemoral joint. They had less severe knee pain, as indicated by lower pain intensity, shorter symptom duration and better KOOS scores, compared to participants in previous studies
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Fig 2. Mechanical PPTs at the three test sites before the conditioning stimulus.
]. The lower severity might have been reflected in their PPT scores. This is supported
by the subgroup analysis stratified on pain intensity and symptom duration, where the lowest
PPT scores were seen among patients with the highest pain intensity. This is similar to
Coombes et al who showed that higher severity of symptoms in lateral epicondyalgia was
linked with larger differences in mechanical hyperalgesia [
]. The explorative plot in Fig 4
demonstrating the percentage change in PPTs after the conditioning stimulus does indicate
that those with the shortest duration of symptoms experience the largest changes in PPTs.
Collectively, this may lend further support to previous notions of a graded involvement of the
nervous system based on symptom severity [
Participant age is another key factor differentiating the current study from previous publi
cations. Our participants were older than in prior studies and they developed pain during their
mid-twenties compared to previous studies that included participants who developed pain
during adolescence. Emerging evidence suggests that adolescence and childhood may be
critical periods where pain experiences induce long-lasting effects not observed among adults [
Mechanical PPTs measure hyperalgesia of superficial structures and muscles. Measuring hyperalgesia directly from deep chondral bone in patients with PFP could provide new insights into the manifestiations of peripheral and central manifestations of pain. However to our knowledge, such a method does not exist yet.
Comparison to previous studies
Young female adults (age 20) with long-standing patellofemoral pain (average of 6 years) demonstrated impaired an CPM response compared to pain-free healthy controls . In addition
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Fig 3. Change in PPTs after the conditioning stimulus at the three test sites split into four groups based on a median split of pain intensity
and duration of symptoms among patients with PFP.
to age and symptom duration, the study by Rathleff et al used a cuff pressure around the lower
leg as the conditioning stimulus. The type of conditioning stimulus can influence the CPM
effect. Oono et al. [
] recently showed that CPM paradigms with different test stimuli may
yield very different results. They found that among the same participants, CPM may range
from 0.5% and up to 37%. The strongest CPM effect was observed using a cold pressor test
similar to the present study while a lower effect was observed with a cuff pressure. Despite
using a potent conditioning stimulus (CPM range: 6.3±13.5%), we did not observe an impaired
CPM in this population compared to controls.
Strengths and limitations
Before we conducted the study, we assessed the reliability of the PPT outcomes and CPM
paradigm. Our methods proved to be reliable which suggest that lack of differences in outcome
measures between groups was not just attributed to error. Likewise, we used a blinded
outcome assessor to minimize the risk of detection bias. We did not collect a blinding index for
the outcome assessor, which makes it difficult to ascertain the success of blinding. Due to time
constraints, we recruited 5 subjects less than planned 70. This is unlikely to affect any of our
We recruited participants who volunteered through advertising. These participants were not recruited through their contact with a medical practitioner or physiotherapist. We did not
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Fig 4. Mechanical PPTs at the three test sites split into four groups based on a median split of pain intensity and duration of symptoms
among patients with PFP.
ascertain if they were actively seeking treatment, which might limit generalisation of this data
to those seeking intervention. While the pain levels are lower than other studies, arguably a
mean 5/10 pain NRS (IQR: 3 to 7) in our PFP participants is of the order expected to be of
concern to the individual and underpins the relevance of our findings. To further investigate the
association between symptom severity and pain sensitisation, larger sample-sizes are needed.
As this study was not designed as an equivalence study, larger studies are needed to confirm the lack of difference between groups within a population similar to the current.
We found no difference in CPM between adults with PFP and age and sex matched pain-free controls. Collectively, these results suggest that this group of patients did not exhibit alterations in peripheral or central processing of pain.
S1 File. Mean values for pressure pain thresholds and conditioned pain modulation.
S2 File. Supporting data for results.
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Conceptualization: Michael Skovdal Rathleff, Camilla Rams Rathleff, Aoife Stephenson,
Rebecca Mellor, Mark Matthews, Kay Crossley, Bill Vicenzino.
Data curation: Michael Skovdal Rathleff, Camilla Rams Rathleff, Rebecca Mellor, Mark Matthews, Bill Vicenzino.
Formal analysis: Michael Skovdal Rathleff, Camilla Rams Rathleff, Rebecca Mellor, Mark
Matthews, Bill Vicenzino.
Funding acquisition: Michael Skovdal Rathleff.
Investigation: Michael Skovdal Rathleff, Camilla Rams Rathleff, Rebecca Mellor, Mark Matthews, Kay Crossley, Bill Vicenzino.
Methodology: Michael Skovdal Rathleff, Camilla Rams Rathleff, Aoife Stephenson, Rebecca
Mellor, Mark Matthews, Kay Crossley, Bill Vicenzino.
Project administration: Michael Skovdal Rathleff, Aoife Stephenson, Rebecca Mellor, Mark
Matthews, Kay Crossley, Bill Vicenzino.
Supervision: Kay Crossley, Bill Vicenzino.
Validation: Aoife Stephenson, Rebecca Mellor, Mark Matthews.
Writing ± original draft: Michael Skovdal Rathleff, Camilla Rams Rathleff, Aoife Stephenson,
Writing ± review & editing: Michael Skovdal Rathleff, Camilla Rams Rathleff, Aoife Stephenson, Rebecca Mellor, Mark Matthews, Kay Crossley, Bill Vicenzino.
10 / 12
11 / 12
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