Larsen et al.

Trials (2020) 21:218

https://doi.org/10.1186/s13063-020-4126-5

STUDY PROTOCOL Open Access

Neuromuscular exercise and pain

neuroscience education compared with
pain neuroscience education alone in
patients with chronic pain after primary
total knee arthroplasty: study protocol for
the NEPNEP randomized controlled trial
Jesper Bie Larsen1,2* , Søren T. Skou3,4, Lars Arendt-Nielsen1, Ole Simonsen5 and Pascal Madeleine2

Abstract
Background: Total knee arthroplasty (TKA) is considered an effective treatment for pain relief and improved
physical performances in end-stage knee osteoarthritis. However, several studies have reported less favorable
outcomes after TKA with chronic pain rates of approximately 20%. Exercise might be an effective treatment strategy
for chronic pain following TKA, but no randomized controlled trials have evaluated its effect. Therefore, the purpose
of this randomized controlled trial is to investigate whether a 12-week neuromuscular exercise (NEuroMuscular
EXercise training program for patients with knee or hip osteoarthritis assigned for total joint replacement; NEMEX-
TJR) program combined with pain neuroscience education (PNE) provides greater pain relief and improvement in
physical performances than PNE alone at 12 months follow-up in a population of patients with chronic pain after
primary TKA.
Methods: For this randomized controlled superiority trial, 120 patients with moderate-to-severe chronic pain after
TKA are recruited from Aalborg University Hospital, Denmark. Patients are randomly assigned in a 1:1 ratio to one of
two interventions: (a) NEMEX-TJR twice weekly for 12 weeks combined with two sessions of PNE or (b) two sessions
of PNE given over 6 weeks. Assessment is performed at baseline before intervention and at 3, 6, and 12 months
after initiation of the intervention. Outcome assessors are blinded toward group allocation. The primary outcome is
the change in the Knee Injury and Osteoarthritis Outcome Score4 (KOOS4), defined as the mean score for the KOOS
subscales pain, symptoms, activities of daily living, and quality of life. Secondary outcomes include all KOOS
subscale scores and scores for PainDETECT, the Fear-Avoidance Beliefs Questionnaire, Global Perceived Effect, the
Pain Catastrophizing Scale, pain intensities, temporal summation, conditioned pain modulation, and pressure pain
thresholds. Physical performances are measured with walking, stair climbing, and chair standing tests as well as
tests of muscle strength and power.
(Continued on next page)

* Correspondence: [email protected]
1
Translational Pain Biomarker, SMI, Department of Health Science and
Technology, School of Medicine, Aalborg University, Aalborg, Denmark
2
Sports Sciences – Performance and Technology, Department of Health
Science and Technology, School of Medicine, Aalborg University, Aalborg,
Denmark
Full list of author information is available at the end of the article

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Larsen et al. Trials (2020) 21:218 Page 2 of 10

(Continued from previous page)

Discussion: The findings will be useful in establishing effective treatment strategies for chronic pain after TKA. The
randomized controlled trial involves rigorous scientific methods and uses clinically applicable interventions. The
study interventions are conducted in clinical settings, thereby enhancing the possibility of future implementation of
the treatments in the health care systems.
Trial registration: ClinicalTrials.gov identifier: NCT03886259. Registered 22 March 2019. Ethics committee
registration: N-20180046.
Keywords: Total knee replacement, Chronic pain, Neuromuscular exercise, Pain neuroscience education

Background activation and loading of muscles, and postural control

Osteoarthritis (OA) is considered the most frequent cause [14, 16]. Such a focus could also be relevant for patients
of disability and pain in the elderly population, and the with chronic pain after TKA. However, it is unknown
knee joint is one of the joints most commonly affected [1, whether the NEMEX-TJR program or any other exercise
2]. End-stage knee OA is often treated with a knee re- program is effective in a population of patients with
placement. Total knee arthroplasty (TKA) is considered chronic pain and impaired physical performance after
an effective treatment for pain relief and improved phys- TKA, highlighting the need for high-quality clinical trials.
ical performance [3, 4]. However, less favorable outcomes Over the last few years, a shift in patient information
such as chronic pain have been reported in approximately from the biomedical model to a biopsychosocial model has
20% of patients undergoing TKA [5]. Chronic pain in OA been proposed as education for chronic pain patients [17,
patients is believed to occur as a result of local patho- 18]. Since sensitization is a frequent phenomenon in
logical processes in and around the joint, genetic and chronic pain patients, a new approach to education is
metabolic factors and neuronal changes at several levels, needed – one that targets pain neuroscience instead of fo-
including peripheral or central sensitization, reduced de- cusing on the nociceptive pain [17]. Pain neuroscience edu-
scending inhibition, and atrophy of cortical areas [6]. cation (PNE) has the potential to decrease anxiety and fear
These mechanisms are considered important for the de- of movement after surgery and could therefore be useful
velopment of chronic pain after TKA [7, 8]. for patients experiencing chronic pain after TKA [19]. Pain
A systematic review reported that 20% of patients felt neuroscience education seems to provide the best results
that TKA surgery had not been successful enough to when delivered in conjunction with exercises, as these two
resume their regular activities of daily living (ADL), in- treatments modalities might optimize each other [20].
cluding walking, stair climbing, dressing, and getting in We initiated the NEPNEP (Neuromuscular Exercises and
and out of bed [9]. Therefore, the rehabilitation of pa- Pain Neuroscience Education for chronic Pain) trial with
tients with chronic pain after TKA needs to aim for both the purpose of evaluating whether a 12-week NEMEX-TJR
reducing pain and improving physical performance. program combined with PNE provides greater pain relief
Guidelines for knee OA have established exercise as an and improvement in physical performances than PNE alone
effective treatment for both pain and functional impair- in a population of patients with chronic pain after primary
ment [10, 11]. For patients suffering from chronic pain TKA. We hypothesize that NEMEX-TJR and PNE in com-
after TKA, no such guidelines or standardized treatment bination can provide greater pain relief and better physical
regime exist. This is emphasized in two recent systematic performance compared to PNE alone after 12 months.
reviews, summarizing the evidence regarding the treat-
ment of chronic pain after TKA and reporting the absence Methods/design
of randomized controlled trials evaluating the effects of Study design
exercise therapy and other treatments [12, 13]. This study is a randomized controlled superiority trial
A neuromuscular exercise (NEuroMuscular EXercise with blinding of both the outcome assessor and the
training program for patients with knee or hip osteoarthritis statistician analyzing the data. This study protocol fol-
assigned for total joint replacement; NEMEX-TJR) program lows the recommendations of the SPIRIT (Standard
developed by Ageberg et al. (2010) has been shown to be Protocol Items: Recommendations for Interventional
feasible and effective in treating pain and impaired function Trials) guideline [21] (see supplementary file 1). In con-
in patients with end-stage knee OA and immediately fol- junction with the SPIRIT guideline, specific interven-
lowing TKA surgery [14, 15]. The NEMEX-TJR program tions were described based on the TIDieR (Template for
aims at improving sensorimotor control and functional Intervention Description and Replication) checklist [22]
joint stability by using weight-bearing exercises with a focus and the CERT (Consensus on Exercise Reporting Tem-
on the quality and alignment of movements, optimal plate) checklist [23] (see supplementary file 2).
Larsen et al. Trials (2020) 21:218 Page 3 of 10

Ethical considerations Ethics, Aalborg as soon as the principal investigator has

The trial is being conducted in accordance with the been alerted.
Helsinki Declaration, has been approved by the local
ethics committee (the North Denmark Region Commit-
tee on Health Research Ethics, Aalborg, N-20180046), Participants and settings
and is registered at ClinicalTrials.gov (NCT03886259; A total of 120 patients will be recruited from the ortho-
https://clinicaltrials.gov/ct2/show/NCT03886259). Any pedic surgical department at Aalborg University Hos-
changes to the trial protocol will be communicated to pital. Patients will be recruited from the hospital's
the ethics committee and the clinical trial registry. All patient research database and from screening patients
patients will be thoroughly informed about the trial be- referred to the involved orthopedic departments. To fa-
fore inclusion and will sign informed consent forms be- cilitate patient enrollment it will be possible to partici-
fore participation. The NEMEX-TJR program used in pate at one of the three local Departments of
the current trial has been found to be feasible and safe Occupational and Physiotherapy from the northern re-
to use [14]. No adverse events, besides possible tempor- gion of Denmark, thereby covering a larger geographical
ary soreness after the NEMEX-TJR program, are ex- area. Patients will have their travel expenses reimbursed
pected and therefore, no data monitoring committee to avoid social inequality and increase adherence. Pa-
has been established. If any serious adverse events tients will be randomly assigned in a 1:1 ratio to undergo
occur during the trial, these will be reported to the either 12 weeks of NEMEX-TJR combined with PNE or
North Denmark Region Committee on Health Research PNE alone. A flow diagram is presented in Fig. 1.

Fig. 1 Flow diagram

Larsen et al. Trials (2020) 21:218 Page 4 of 10

Patients will be eligible for inclusion if they meet the Randomization and allocation concealment
following criteria: The patients will be randomized in a 1:1 ratio to one of
two treatment arms: (1) NEMEX-TJR and PNE or (2)
 male or female aged 40 to 80 years; PNE alone. Using computer-generated random numbers
 body mass index (BMI) between 19 and 40 kg/m2; in permuted blocks of four to eight patients, the project
 primary TKA due to OA ≥ 12 months manager will randomly assign patients to either of the
postoperatively; treatment arms after the informed consent has been
 for the index knee, a duration of knee pain > 6 signed and the baseline assessment conducted.
months; and
 for the index knee, an average daily pain score ≥ 4 Interventions
(moderate-to-severe pain) on a numeric rating scale Patients will participate in the interventions at the local
(NRS; 0 (no pain) to 10 (maximum pain)) over the Departments of Occupational and Physiotherapy in the
last week prior to recruitment. northern region of Denmark. These departments are
part of the Aalborg University Hospital, Denmark.
Patients having the following attributes will be ex- Patients in the exercise and PNE group will receive a 12-
cluded from the trial: week rehabilitation program consisting of the NEMEX-
TJR program [14]. The NEMEX-TJR program will be
 chronic pain due to loosening of implant or conducted as a 1-hour, group-based session twice a week
prosthesis failure requiring revision surgery; for 12 weeks (24 sessions in all). Physiotherapists specific-
 secondary causes of arthritis to the knee, such as ally trained to conduct the intervention will instruct and
rheumatoid arthritis or sequelae from previous supervise the patients during the neuromuscular exercises,
accidents; including individualization of the load and exercise diffi-
 surgery (including arthroscopy) of the index knee culty based on each patient’s physical ability and pain in-
within 3 months prior to recruitment; tensity. Exercises will be initiated by a warm-up session
 injury to the index knee within 12 months prior to consisting of 10 minutes of ergometer cycling at a self-
visit; selected intensity, followed by a circuit program consisting
 acute pain, other than in the index knee, affecting of exercises such as pelvic lifts, sit-ups, sliding exercises,
the lower limb and/or trunk at the time of baseline lunges, rubber band exercises, chair stands, and stair climb-
testing; ing, with walking as a cool-down exercise. Exercises will be
 participation in other pain trials 2 weeks prior to performed in two to three sets of 10 to 15 repetitions, with
recruitment; a short rest between each set and exercise. Exercises will
 pregnancy; be initiated at level 1 and could progress to levels 2 and 3.
 drug and alcohol abuse; Progression (e.g. increasing the load or range of movement
 rheumatoid arthritis, neurologic illnesses or primary or changing the support surface) will be applied if the exer-
pain area other than knee (e.g. low back pain or cises are performed with high-quality and sensorimotor
upper extremity pain); or control based on visual inspection by the physiotherapist
 lack of ability to adhere to protocol. and if patients perceive the exercises as requiring minimal
effort [14]. Pain intensity during and after training will be
Sample size monitored. Due to the chronicity of the patients’ pain, a
Based on the literature, a minimal clinically important dif- time-contingent approach to the exercises is preferred over
ference of 10 points in the Knee injury and Osteoarthritis a symptom-contingent method [26]. If a major flare-up in
Outcome Score (KOOS) is commonly used [24]. The sam- pain levels is experienced, the intensity and volume of
ple size calculation was based on the KOOS4 and defined training will be reduced until symptoms are “as usual” [14].
as the mean score for the KOOS subscales of pain, symp- Both treatments groups will receive the same PNE
toms, ADL, and quality of life. A sample size calculation consisting of two group-based educational sessions: one
was conducted to obtain a study power of 90% to detect a at the start of the trial period and one 6 weeks after the
minimum improvement of 10 points on the KOOS4 in the initiation of the trial. Both sessions will take 1 hour and
NEMEX-TJR and PNE group compared with the PNE be conducted by a physiotherapist trained in PNE. The
group (with a standard deviation [SD] of 15) [15, 25]. A sessions cover topics concerning the multifactorial na-
two-sided significance level at 0.05 was applied. The calcu- ture of chronic pain, sensitization, hyperalgesia, allody-
lation revealed that 49 patients will be required in each nia, and plasticity of the brain, aiming at giving patients
group. To account for possible missing data and a 20% a better understanding of their chronic pain and thereby
loss from patients missing follow-ups, a total of 60 pa- engaging the patients in the treatment. Information leaf-
tients will be included in each group. lets summing up the PNE topics will be handed out to
Larsen et al. Trials (2020) 21:218 Page 5 of 10

the patients after the PNE sessions. During the sessions, intensity over the last week prior to the visit and the
it will be possible to ask questions and share experiences maximal pain intensity during rest (day and night), walk-
within the patient group. ing, and stair climbing. Patients will also be asked to
draw their habitual pain distribution on anatomical body
Assessments and blinding maps [34]. A handheld algometer (Somedic, Hörby,
Baseline measurements will be completed prior to Sweden) with a 1-cm2 probe will be used to record the
randomization and follow-up measurements will be pressure pain threshold (PPT) in kPa, which can be reli-
conducted at 3, 6, and 12 months after initiation of the ably assessed using pressure algometry [35, 36]. The
intervention. All assessment will take place at the De- pressure will be increased gradually at a rate of 30 kPa/s
partment of Occupational and Physiotherapy, Aalborg until the pain threshold is reached and the patient
University Hospital, Denmark (see Fig. 2). Trained out- presses a stop button. The PPTs will be measured three
come assessors, blinded toward treatment allocation, times for each point with an interval of a minimum of
will perform all assessments. Before the follow-up as- 20 seconds between each PPT assessment. The average
sessments, patients will be asked not to mention which of the three PPTs will be calculated for further analysis.
treatment group they have been assigned to in order to Bedside tests for sensitization consist of pinprick hyper-
maintain blinding. Demographic measures include gen- algesia, temporal summation, dynamic mechanic allody-
der, age, height, body mass, BMI, index knee, dominant nia, and deep somatic hyperalgesia. A single pinprick
leg, time since surgery, comorbidities, and scores on with a nylon filament (0.7 mm, Chicago Medical Supply)
the Hospital Anxiety and Depression Scale [27]. will be applied perpendicularly to the skin (until slight
bending of the filament occurs, when a force of 75 gram is
Outcomes applied) and the patients rated the pain intensity on an
Primary outcome NRS. Temporal summation will be measured using the
Knee Injury and Osteoarthritis Outcome Score4 nylon filament (0.7 mm) applied 10 times in an area of 1
(KOOS4) The primary outcome will be the change from cm2 with a frequency of 1/s. Then, the patients will rate
baseline to 12 months in KOOS4, which will be an the intensity of the last stimulus on an NRS. Dynamic
average of the four subscales of pain, symptoms, ADL, mechanical allodynia will be examined using a cotton
and quality of life from the patient-reported outcome swab stroked four times on the skin (twice from each
measure KOOS. The KOOS4 ranges from 0 (worst) to direction of a cross with 90° angles). The length of each
100 (best) [24]. A minimum change of 10 points is stroke will be 3–5 cm. The patients will rate the pain in-
considered clinically relevant [25]. tensity induced by the stroke on an NRS. Deep somatic
hyperalgesia will be measured using a bedside pressure
Secondary outcomes algometer (syringe). The air in the syringe will be com-
Patient-reported outcome measures Several patient- pressed at a constant speed (1 ml/s) until the pressure be-
reported outcome measures will be collected (Fig. 2). comes painful. The patients will be asked to indicate when
The scores on all five KOOS subscales, including the the pressure became painful (threshold in ml). Pressure
sport-recreation subscale, will be included to support pain thresholds and bedside tests for sensitization will be
the clinical interpretation of the primary outcome [28]. recorded in the area of the index knee, adjacent to the
The PainDETECT questionnaire is a screening tool that knee (10 cm above the knee, ventral thigh), and extra-
predicts the likelihood of a neuropathic pain component segmentally on the medial side of the forearm (muscle
in chronic pain disorders [29]. The Fear-Avoidance Be- belly of the flexor digitorum superficialis). Conditioned
liefs Questionnaire – Physical Activity is a four-item pain modulation will be assessed using PPT as test stimuli
questionnaire for which a high score indicates a high de- and a spring-based pressure clamp applying a force of 1.3
gree of fear-avoidance beliefs [30, 31]. Global perceived kg as conditioning stimuli. Test stimuli will be applied to
effect will be assessed using the question: “How are your the middle part of the tibialis anterior muscle of the non-
knee problems now compared with before you entered affected side and conditioning stimuli will be applied to
this study?” The question will be answered on a 7-point the ipsilateral earlobe. The patients will be asked to report
Likert scale ranging from “improved, an important im- their use of pain medication during last week (yes/no), in-
provement” to “worse, an important worsening” [32]. cluding the number of paracetamols (1 g), ibuprofen (400
The Pain Catastrophizing Scale is a 13-item question- mg), and other nonsteroidal anti-inflammatory drugs.
naire developed to explore how catastrophizing affects
pain experiences [33]. Physical performance measures Five objective physical
performance measures will be collected (Fig. 2). Based
Pain-related outcome measures Pain intensity ratings on the Osteoarthritis Research Society Internationals
will be measured using NRS for the average daily pain core recommendations for physical performance
Larsen et al. Trials (2020) 21:218 Page 6 of 10

Fig. 2 SPIRIT figure showing schedule of enrolment, interventions, and trial outcomes to be assessed
Larsen et al. Trials (2020) 21:218 Page 7 of 10

measures, a 40-meter fast-paced walk test, a stair climb therefore, aim at using a repeated measures mixed
test, and a 30-second chair stand test will be performed model with patients as random effect and time (baseline
[37]. Leg extension power (Nottingham Power Rig, Not- and 3, 6, and 12 months) and treatment arm (NEMEX-
tingham, UK) expressed as the product of force and vel- TJR and PNE or PNE alone) as fixed effects, and with
ocity in a single-leg simultaneous hip and knee adjustments for baseline imbalance. No imputation will
extension will be measured. The force will be recorded take place. Secondary outcomes and other endpoints will
for each push (with 30 seconds rest between trials) until be analyzed similarly to the primary outcome. The fre-
the patients reach a plateau, defined as two successive quency of adverse events will be compared between
measurements below the highest measurement. A mini- groups at the 12-month follow-up using a Poisson re-
mum of six trials to minimize the learning effect and a gression model with robust error variance. Categorical
maximum of 12 trials to minimize fatigue will be con- outcomes will be analyzed using a Χ2 test, Fisher exact
ducted and peak measurements in Watts obtained, test, or a Mann-Whitney U test as appropriate. A per-
which is a methodology used frequently and illustrating protocol analysis will be performed for the primary out-
excellent reliability [38–40]. Maximal voluntary force come, excluding patients who had poor adherence to the
from the knee extensors and flexors will be measured bi- intervention, defined as participating in less than 75% of
laterally in isometric conditions with a handheld dyna- the exercise sessions and not attending both PNE ses-
mometer (Lafayette Manual Muscle Tester, sions, and excluding patients who undergo additional
Loughborough, UK or MicroFET2, Hoggan Scientific, surgery during follow-up. A 95% confidence interval (CI)
LLC, Salt Lake City UT, USA). The patients will be excluding 10 points or more in the KOOS4 score will be
asked to exert a maximum voluntary isometric contrac- interpreted as a lack of a clinically meaningful difference
tion lasting 5 seconds against the hand-held dynamom- between groups. P values and 95% CIs will be presented.
eter. Three trials of each test will be performed and the All authors will have access to the final anonymized trial
peak value in Newtons will be the outcome score, which dataset.
is an approach that has illustrated excellent test-retest
reliability [41]. A 30-second break between each meas- Trial steering committee
urement will be given. See title page for members of the trial steering commit-
tee. All members participated in the conception of the
Other outcomes Adverse events that may occurr during study design and procured funding. The principal inves-
the trial period will be identified by the patients (self-re- tigator (JBL) is coordinating the ongoing trial. The trial
ported) and by the physiotherapists supervising the inter- steering committee reviews the progress of the trial and
ventions (observations). Adverse events are characterized agrees the necessary changes in the protocol, if any.
as occurring in the index knee or sites other than the
index knee and serious events are defined according to Data collection and management
the definitions from the U.S. Food and Drug Administra- All obtained results will be collected using a test score
tion [42]. Non-serious adverse events are comprised of all protocol or fulfilling questionnaires and thereafter, en-
other occurring events. Participants are allowed to receive tered into Excel (version 2016, Microsoft Corporation,
other types of treatment at their own discretion. The other Redmond, WA, USA). From Excel, data will be trans-
types of treatment received during the trial period will be ferred into SPSS version 25.0 (SPSS Inc., Chicago, IL,
self-reported. Other treatment is defined as treatments USA) for statistical analyses. All collected test score pro-
that the patient had initiated because of the index knee tocols and questionnaires will be kept in a locked place
such as acupuncture, manual therapy, and surgery. Adher- as back up. Anonymized study data in electronically for-
ence to interventions will be registered for both groups. In mat will be stored at an encrypted network. Access to
the NEMEX-TJR and PNE group, the number of study data is restricted and cannot be accessed without
attended exercise sessions and PNE sessions will be permission.
recorded (i.e. number of sessions out of 24 exercises
sessions and two PNE sessions). In the PNE group, Audit
the number of PNE sessions will be recorded (i.e. The North Denmark Region Committee on Health Re-
number of sessions out of two possible sessions). search Ethics selects a number of approved studies for
audit every year. These audits are independent from the
Statistics trial steering committee and possible study sponsors.
The statistical analysis of the primary outcome will be
performed according to an intention-to-treat principle. Publication
Statistical tests will be dependent of data distribution. Results will be published regardless of outcome. Author-
We expect data to be normally distributed, and ship will be determined based on the guidelines from
Larsen et al. Trials (2020) 21:218 Page 8 of 10

the International Committee of Medical Journal Editors. thoroughly studied in trials of exercise and education as
The authors do not have any publication restrictions. treatment of knee pain [49]. Finally, no process or eco-
nomic evaluation will be conducted within the present
Discussion trial. Such evaluations will be important to ease and justify
The aim of this trial is to evaluate the effects of a treat- a more general implementation of the NEPNEP interven-
ment that could potentially relieve pain and improve tion in TKA patients suffering from chronic pain.
physical performance as well as provide education to as-
sist patients in handling their chronic pain and disability.
Trial status
This is of definite importance since no other randomized
The trial is ongoing and is currently recruiting patients.
controlled trial has been conducted regarding exercise as
Recruitment was initiated on April 12, 2019 and is ex-
treatment for chronic pain after TKA [12, 13]. The trial
pected to be completed by the end of December 2021.
builds on the presence of sensitization in several studies
This protocol is based on protocol version 4.0 of the 16
examining painful knee OA and chronic pain after TKA
August 2018. The trial was registered with Clinical-
[7, 43–46] and evaluates if it is possible to modulate
Trials.gov (NCT03886259) on the 22 March 2019.
sensitization outcomes by using NEMEX-TJR in com-
bination with PNE.
The strengths of the trial are the use of rigorous Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
methods that include randomized allocation, blinding of
1186/s13063-020-4126-5.
outcome assessors, and the use of clinical applicable in-
terventions. The trial interventions are conducted in Additional file 1. SPIRIT 2013 Checklist for the NEPNEP trial.
clinical settings, thereby enhancing potential future im- Additional file 2. The TIDieR (Template for Intervention Description and
plementation of the treatments in health care systems. Replication) Checklist for the NEPNEP trial.
There are some potential limitations of the trial. Since
the patients have chronic pain, some may use pain medi-
Abbreviations
cation. This could interfere with the assessment of pain. ADL: Activities of daily living; BMI: Body mass index; CERT: Consensus on
In order to reduce possible bias from this, the use and Exercise Reporting Template; CI: Confidence interval; KOOS: Knee injury and
Osteoarthritis Outcome Score; NEMEX-TJR: NEuroMuscular EXercise
dosage of medication will be assessed, allowing the study
training program for patients with knee or hip osteoarthritis assigned for
group to evaluate whether the use of pain medication in- total joint replacement; NRS: Numerical rating scale; OA: Osteoarthritis;
creased or declined during the trial. Chronic pain pa- PNE: Pain neuroscience education; PPT: Pressure pain threshold; SD: Standard
deviation; SPIRIT: Standard Protocol Items: Recommendations for
tients often have comorbidities or other painful
Interventional Trials; TIDieR: Template for Intervention Description and
musculoskeletal disorders [47] that may influence how Replication; TKA: Total knee arthroplasty
they respond to the interventions. One way to avoid this
influence would be to sample a population of patients Acknowledgements
with no other pain sites or comorbidities besides knee The Physiotherapy Department at Aalborg University Hospital, Denmark is
acknowledged for administrative and logistic support. We thank the project
pain following TKA. Such a homogeneous group would workers Jannie Damsgaard Nørlev, Mikkel Skinderholm, Inge Marie Melgaard,
not reflect real-life patients and therefore, the results Laila Kragh Thøgersen, Vibeke Holm Pedersen, Nadja Kostending Pedersen,
would not be generalizable. Due to their chronic pain Mette Højsleth Nielsen, Kasper Frank Frederiksen, and Kristine Bugge
Hæstrup for assisting in recruitment, treatment, and data collection, and we
and disabilities, patients might decide to seek help or thank the patients for their contributions to the study.
other treatments during the trial. Patients who receive STS is currently funded by a grant from Region Zealand and a grant from
PNE alone might be more interested in seeking other the European Research Council (ERC) under the European Union’s Horizon
2020 research and innovation program (grant agreement No 801790).
treatments than the exercise group, which will already
be receiving additional treatment twice a week. If this
Authors’ contributions
occurs, it might counterbalance the possible differences JBL is the principal investigator and coordinating the trial. JBL, STS, LAN, OS,
between the groups. To avoid this bias, we will collect and PM participated in the conception of the study design and procured
data on other treatments received during the trial funding. JBL wrote this manuscript and all authors provided feedback, read,
and approved the final manuscript.
period, which will allow us to evaluate whether this par-
ameter might have had an impact. Since the group re-
Funding
ceiving NEMEX-TJR in combination with PNE has 24 The Danish Rheumatism Association and the Svend Andersen Foundation is
more sessions with the physiotherapist, there is an inher- acknowledged for their individual and independent funding. The study
ent risk that part of the explanation for a possible larger sponsors will have no involvement in executing the trial, interpreting the
data, or publishing the results.
effect in this group will be due to the increased attention
that they receive alongside a stronger patient-practitioner
Availability of data and materials
interaction [48]. Large contributions from contextual fac- The data sets used and analyzed during the trial will be available from the
tors have been observed in treatment effects, although not principal investigator on reasonable request.
Larsen et al. Trials (2020) 21:218 Page 9 of 10

Ethics approval and consent to participate 15. Skou ST, Roos EM, Laursen MB, Rathleff MS, Arendt-Nielsen L, Simonsen O,
The trial is approved by the North Denmark Region Committee on Health et al. A randomized, controlled trial of total knee replacement. N Engl J
Research Ethics (N-20180046) and by the Danish Data Protection Agency. All Med. 2015;373(17):1597–606.
participants will sign informed consent before participation. 16. Ageberg E, Roos EM. Neuromuscular exercise as treatment of degenerative
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Consent for publication perspective on pain neuroscience education in physical therapy. J Orthop
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not-for-profit initiative hosted at University of Southern Denmark, aiming at 19. Louw A, Diener I, Butler DS, Puentedura EJ. Preoperative education addressing
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