Abstract
Objective
This study investigated the effects of neuromuscular exercises and pain neuroscience education (PNE) compared with PNE alone on muscle strength and power in patients with chronic pain after total knee arthroplasty (TKA).
Design
Secondary analysis of a randomized controlled trial. Patients with chronic pain for >1-year after TKA were randomized to supervised neuromuscular exercises with PNE or PNE alone. The neuromuscular exercise group underwent 24 sessions over 12-weeks. The PNE was delivered in two 1-h group sessions, identical in the two groups. Outcomes included maximum voluntary isometric contractions for knee extensors and flexors, peak leg extension power and the Knee injury and Osteoarthritis Outcome Score (KOOS). Outcomes were measured at baseline, 3, 6, and 12-months. Analysis was conducted using repeated measures mixed models. Multivariable linear regression, with groups collapsed into one, was conducted to evaluate associations.
Results
Sixty-nine participants were enrolled, 36 in the exercise and PNE group and 33 in the PNE alone group. No significant between-group differences were found in changes from baseline to 12-months for muscle strength or leg extension power. The exercise and PNE group showed significant within-group improvements in leg extension power (26.3 W, p = 0.019) and knee flexor strength (19.7 N, p = 0.001), which was not observed in the PNE alone group. No significant associations were found between changes in muscle strength or power and changes in KOOS.
Conclusions
Neuromuscular exercises and PNE do not seem to provide superior improvements in muscle strength or power compared to PNE alone in patients with chronic pain after TKA.
Trial registry
The trial was pre-registered at ClinicalTrials.gov (NCT03886259).
Keywords: Exercise, Muscle strength, Total knee arthroplasty, Chronic pain
1. Introduction
Knee osteoarthritis is a prevalent condition affecting more than 360 million worldwide [1]. Total knee arthroplasty (TKA) is a common treatment for end-stage knee osteoarthritis [2]. Although considered an effective treatment, providing pain relief and improving physical function, up to 20% of patients experience chronic pain after TKA [[2], [3], [4]]. Furthermore, physical function is also impaired in patients with chronic pain after TKA [5,6]. Chronic pain after TKA is considered multifactorial and can be influenced by physiological factors including central pain mechanisms and psychosocial factors [7,8]. Overall, there is a knowledge gap concerning effective treatment of chronic pain after TKA [9,10]. Low quadriceps muscle strength has been associated with pain after TKA [11] and it is well-established that quadriceps and hamstring muscle strength and power are markedly decreased following TKA surgery [[12], [13], [14], [15], [16], [17]]. This postoperative impairment in muscle strength and power is suggested to be caused by arthrogenic muscle inhibition [13,18,19]. It is believed that arthrogenic muscle inhibition is caused by changes in the discharge of sensory receptors in or around the damaged knee joint, leading to altered excitability of spinal and supraspinal pathways, resulting in impaired muscle activation [13,18]. Associations between muscle strength and function (e.g., walking and stair climbing) have been observed, highlighting the importance of muscle strength in relation to postsurgical pain and function [11,16,20,21]. Further, power is associated with performance and function after TKA [22]. Hence, postsurgical rehabilitation is frequently used after TKA to optimize muscle strength, power and function [23]. However, despite improvements following postsurgical rehabilitation, studies have shown that the muscle strength in the TKA leg continues to be markedly impaired compared with controls [14,15]. Apart from the effects on muscle strength and power, exercises are also reported to decrease pain intensity and sensitivity. The proposed mechanisms behind the effect of exercising on chronic pain are related to effects on the central nervous system, systemic effects and psychological effects [[24], [25], [26]]. Similarly, pain neuroscience education (PNE) has been suggested to decrease levels of pain catastrophizing and kinesiophobia [27,28].
Most research has been conducted in TKA populations without chronic pain and no studies have investigated whether exercise can improve muscle strength and power in patients with chronic pain after TKA or the derived effects of improved muscle strength and power on chronic pain after TKA. Progressive resistance training [19] and neuromuscular exercises are feasible for patients after TKA [29,30] but have never been investigated in patients with chronic pain after TKA. To avoid inducing pain flare-ups in a population already experiencing high levels of pain [5], we choose neuromuscular exercises as rehabilitation for the patients with chronic pain after TKA. This was based on our clinical experiences on rehabilitation for this patient population.
Therefore, this secondary analysis aimed to investigate whether supervised neuromuscular exercise and PNE could improve quadriceps and hamstring muscle strength and leg extension power more than PNE alone in patients with chronic pain after TKA. The non-exercising PNE alone group, thereby was a control group for the exercise and PNE group. Further, to evaluate the associations for the change in muscle strength, leg extension power and self-reported pain, function and knee-related quality of life.
We hypothesized that the group receiving exercise and PNE would improve their muscle strength and leg extension power significantly more than the PNE alone group. Further, it was hypothesized that muscle strength and leg extension power would be associated with better outcomes of self-reported pain, function and knee-related quality of life.
2. Methods
2.1. Design
This is a secondary trial report of the NEPNEP parallel group randomized controlled superiority trial [6]. It reports the pre-specified exploratory analyses, published in the statistical analysis plan [31] and conforms to the CONSORT statement for reporting randomized controlled trials [32]. TIDieR and CERT checklists were followed to describe the interventions and have previously been published [6]. Comprehensive information of the study methods can be found in the open access protocol [33] and the open access publication of the primary analysis [6]. The trial was conducted in compliance with the Helsinki Declaration and was approved by the North Denmark Region Committee on Health Research Ethics (N-20180046) on the 16th of August 2018. Further, the trial was pre-registered before inclusion of the first participant at ClinicalTrials.gov (NCT03886259).
2.2. Participants
The Aalborg University Hospitals research databases were used to identify TKA participants at least 1-year postoperatively. Eligible participants were contacted by mail and telephone and invited to participate in the study. Patients with primary TKA due to knee osteoarthritis ≥12 months post-operatively, experiencing chronic pain in the index knee for a duration of ≥6 months and an average daily pain score of ≥4 (moderate-to-severe pain) on a numeric rating scale (Numeric Rating Scale; 0 (no pain) to 10 (maximum pain)) over the last week were recruited. Patients with chronic pain due to loosening of or prosthesis failure were excluded. The patients participated in the interventions at one of three outpatient clinics at Aalborg University Hospital (Farsoe, Thisted or Aalborg). Patients were recruited between April 2019 to October 2022. All patients signed informed consent before being included in the trial.
2.3. Patient involvement
One female and one male patient with chronic pain after TKA were involved during the development of the study. The patients were identified using the hospital research database and were invited to contribute to the design of the study. Their participation was not compensated. The patients gave feedback on the planned study procedures, interventions and outcome measures and the information material. Their feedback was used to both validate the planned setup and to revise information material for it to be described in understandable layman terms.
2.4. Randomization
The recruited patients were randomized in a 1:1 ratio and allocated to receive either 1) neuromuscular exercises and PNE or 2) PNE alone. Patients were randomized using computer-generated random numbers in permuted blocks of 4–8 patients [33].
2.5. Interventions
Participants randomized to neuromuscular exercise received a 12-week program [29] delivered as 1-h, group-based sessions twice a week. The group size was 2–4 participants. All the neuromuscular exercise sessions were supervised by trained physiotherapists. The exercise difficulty was tailored to the individual participant’s physical ability and pain intensity. The exercise program was initiated at lowest level and progressed to next level when exercises could be performed with good quality and control over the movement [33]. Based on the chronicity and severity of the participant’s pain, a time-contingent approach to the exercises was preferred over a symptom-contingent method [34], allowing participants to continue exercising despite high pain intensity (if the participant was able to cope with the pain) contrary to bringing exercises to a halt when the pain intensity reached a pre-specified level. If participants experienced a major flare-up in pain, the exercise intensity was reduced until pain returned to “as usual”. The neuromuscular exercise program included weightbearing activities, lower limb functional movements with focus on joint alignment and strengthening exercises using rubber bands [29]. The neuromuscular exercise program is described in detail elsewhere [33].
PNE has been suggested as a treatment to improve pain and function in chronic musculoskeletal pain conditions [[25], [26], [27]]. The PNE were conducted as two 1-h, group-based sessions separated by six weeks. Participants in both groups received the same PNE sessions by a physiotherapist trained in PNE. The PNE sessions included topics on changing maladaptive pain cognitions and reconceptualizing the participants pain [34], thereby, aiming at engaging the participants in self-management. Further details for the PNE have been published [6].
2.6. Outcomes
All outcomes were assessed at baseline, 3, 6, and 12-months. Outcome assessments were conducted by trained assessors that were blinded towards treatment allocation and not involved in the study.
2.7. Muscle strength
The maximum muscle strength (force) was measured during maximal voluntary isometric contraction for the knee extensors and knee flexors using a fixated handheld dynamometer (Lafayette Manual Muscle Tester, Loughborough, UK or MicroFET2, Hoggan Scientific, LLC, Salt Lake City UT, USA). Both the index knee (i.e., the knee with chronic pain after TKA) and the non-index knee were evaluated. Participants were sitting with 90° hip and knee flexion and exerted a maximum voluntary isometric contraction lasting approx. five seconds against the hand-held dynamometer. The dynamometer was placed proximal to the ankle joint, and a belt was used to stabilize the position of the limb. The participants performed three trials of knee flexion and knee extension separated by a 30-s break, respectively and the peak force in N was the outcome. Maximum muscle strength assessed using handheld dynamometry has illustrated excellent test-retest reliability [35].
2.8. Leg extension power
Leg extension power was expressed as the product of force and velocity in a single-leg simultaneous hip and knee extension (Nottingham Power Rig, Nottingham, UK). Participants were seated with their arms folded across the chest and the examined leg placed on the footplate. The other foot was placed resting on the floor. The seat was adjusted so the footplate was fully depressed when the leg was fully extended [36]. Participants received audio instructions asking them to push the footplate down as hard and fast as possible. The force exerted was recorded for each push. The participants were given a new attempt until they reached a plateau, which was defined as two successive measurements below the highest measurement achieved. A 30-s rest between each measurement was given to minimize potential effect of fatigue. A minimum of six attempts and a maximum of 12 attempts were given to minimize learning effect and fatigue, respectively. The peak power in W was the outcome. Both knees were evaluated. Measurement of leg extension power has excellent test-retest reliability [36,37].
2.9. Patient-reported pain, function, and knee-related quality of life
Improvement in patient-reported outcomes was measured using the Knee injury and Osteoarthritis Outcome Score, using the mean score of the four subscales pain, symptoms, activities of daily living and knee-related quality of life (KOOS4) [38]. The Knee injury and Osteoarthritis Outcome Score subscale Sport and Recreation was not part of the KOOS4 in line with recommendations for evaluations of patients after TKA [39]. The subscales are scored on a five-point Likert scale and a total KOOS4 score is calculated, ranging from 0 (worst) to 100 (best) [38,39]. Further, serious adverse events were registered using self-report from the participants.
2.10. Statistical analysis
2.10.1. Sample size calculation
The sample size calculation was intended for the primary aim of the randomized controlled superiority trial [6]. It was estimated that the sample size required to detect a minimal clinically important difference of 10-points for the KOOS4 (with a standard deviation of 15), would be 49 participants in each group to achieve a study power of 90% from baseline to 12-months follow-up for the between-group comparison, using a two-sided significance level at 0.05. To account for loss to follow-up, it was planned to include 60 participants in each group. However, the trial was conducted during the COVID-19 pandemic which made recruitment difficult and caused a higher dropout rate than expected. Therefore, the pre-planned number of participants was not reached, and it was decided to stop the trial after recruiting for 42 months. Therefore, the secondary pre-specified analyses presented in this study should be considered exploratory.
2.10.2. Data analysis
The analysis was pre-specified and published in a statistical analysis plan before any analysis was initiated [31]. To evaluate the between-group changes from baseline to 12-months, a repeated measures mixed model was conducted with patients as random effect and time for visit (baseline, 3-, 6-, 12-months) and treatment arm (neuromuscular exercises and PNE or PNE alone) as fixed effects and adjusting for baseline imbalance. Further, interaction between follow-up and treatment arm was included in the models. Model 1 adjusted for patients, follow-up, treatment arm and interaction between follow-up and treatment arm and model 2 further included adjustment for age, sex, and body mass index. The analysis was conducted according to the intention-to-treat principle. A pre-specified per-protocol analysis was conducted, which included the participants that participated in at least 75% (18 out of 24) of the neuromuscular exercise sessions and participated in both PNE sessions. To enhance the interpretability of the between-group differences, Cohen´s d effect sizes were calculated and interpreted as 0.2 = “small”, 0.5 = “medium”, and 0.8 = “large” [40].
A multivariable linear regression model based on the enter method with an adjustment for age, sex, and body mass index was applied to estimate the associations between overall treatment effect (KOOS4, dependent variable) and changes from baseline to 12-months for maximum muscle strength for the knee extensors and flexors, peak leg extension power for the index knee (independent variables). The analysis provided β-coefficients that indicate how strong the independent variables influenced the dependent variable, and R2 estimates, indicating how much variability was explained from the independent variables. Based on the purpose of establishing associations between overall improvement in self-reported pain and function (KOOS4) and muscle strength and power, the two groups were collapsed into one regardless of intervention.
To compare our index knee muscle strength outcomes to existing reference values, the data for the two groups were collapsed and normalized to percentage of bodyweight using the formula: Quadriceps force at 12-months in kg (i.e., converted from N)/bodyweight in kg ∗ 100. Likewise, the data for the index knee leg extension power was normalized to W per kg. bodyweight using the formula: Leg extension power in W at 12-months/bodyweight in kg.
95% confidence intervals (CI) are presented for all outcomes. Two-sided P-values <0.05 was considered significant. All analyses were performed in Stata 18 (StataCorp, USA).
3. Results
Participant flow and dropout are reported in Fig. 1 and the baseline demographics for the included participants can be found in Table 1. Both groups showed similar baseline characteristics with no obvious clinically relevant differences. The 69 participants were included in the intention-to-treat analysis. Twenty-three (64%) participants in the group receiving neuromuscular exercises and PNE and 26 (79%) participants in the group receiving PNE alone, fulfilled the pre-specified adherence to the interventions and were included in the per protocol analysis. For the neuromuscular exercise and PNE group, 24 (67%) participants attended the 12-month follow-up assessment and 22 (67%) from the PNE alone group attended the 12-month follow-up assessment. Baseline characteristics for the participants attending the 12-month assessment and the participants lost to follow-up were comparable and have previously been reported [6]. No serious adverse events were reported during the trial.
Fig. 1.
Flow chart for patient inclusion and retention.
Table 1.
Patient baseline demographics.
| Neuromuscular exercises and pain neuroscience education group (N = 36) | Pain neuroscience education alone group (N = 33) | |
|---|---|---|
| Age (years), median (IQR) | 68.8 (62.7–72.9) | 65.8 (60.1–71.3) |
| Female (n, %) | 22 (61%) | 18 (55%) |
| Body mass (kg), median (IQR) | 93.0 (76.7–103.7) | 95.1 (80.2–108.8) |
| Body mass index (kg/m2), median (IQR) | 33.1 (27.7–36.1) | 33.3 (29.5–36.0) |
| Index knee (right, n, %) | 17 (47%) | 16 (49%) |
| Dominant leg (right, n, %) | 30 (86%) | 30 (91%) |
| Average daily pain intensity over last week (NRS), median (IQR) | 6.0 (5.0–7.0) | 5.0 (4.0–6.0) |
| Time since surgery (years), median (IQR) | 3.2 (1.8–4.9) | 2.7 (1.7–4.3) |
IQR: Interquartile range. NRS: Numerical rating scale; 0 (no pain) to 10 (maximum pain).
The intention-to-treat analysis did not demonstrate a between-group difference in changes from baseline to 12-months follow-up for any of the outcomes (Table 2, Fig. 2). All effect sizes were considered “small” and ranged from 0.06 to 0.40 (Table 2).
Table 2.
Intention-to-treat analysis for the outcomes of the index and non-index knee for change from baseline to 12-months.
| Outcome (number of data pointsneuromuscular exercise and PNE group, number of data pointsPNE alone group)∗ | Changes after neuromuscular exercise and PNE group (95% CI) | Changes after PNE alone group (95% CI) | Between-group difference (model 1) (95% CI) | Between-group difference (model 2) (95% CI) |
P-values for between-group difference (model 2) | Effect size |
|---|---|---|---|---|---|---|
| Maximum muscle strength knee extensors, index knee (N) | 0.2 (−26.6 to 27.0) | 24.3 (−19.4 to 68.0) | −24.1 (−75.3 to 27.1) | −20.9 (−65.8 to 24.0) | 0.361 | −0,22§ |
| Maximum muscle strength knee flexors, index knee (N) | 19.7 (7.6–31.9) | 11.3 (−7.3 to 30.0) | 8.4 (−13.9 to 30.7) | 8.6 (−11.9 to 29.1) | 0.409 | 0.18 |
| Peak leg extension power, index knee (W) | 26.3 (4.3–48.3) | 15.9 (−15.3 to 47.1) | 10.4 (−27.9 to 48.6) | 13.6 (−22.2 to 49.3) | 0.457 | 0.13 |
| Maximum muscle strength knee extensors, non-index knee (N) | −8.7 (−30.5 to 13.0) | −15.3 (−60.6 to 29.9) | 6.6 (−43.6 to 56.8) | 14.1 (−28.6 to 56.7) | 0.518 | 0.06 |
| Maximum muscle strength knee flexors, non-index knee (N) | 1.6 (−14.1 to 17.4) | −19.5 (−39.3 to 0.3) | 21.1 (−4.2 to 46.4) | 19.2 (−6.6 to 44.8) | 0.141 | 0.40 |
| Peak leg extension power, non-index knee (W) | −8.2 (−29.8 to 13.4) | −3.7 (−32.9 to 25.6) | −4.6 (−40.9 to 31.8) | −4.1 (-41.4 to 33.2) | 0.829 | −0.06§ |
Positive and negative changes in strength and power indicate improvement and deterioration, respectively.
There were 144 possible data points for the neuromuscular exercises and PNE group (36 at baseline, 3, 6, and 12-months) and 136 possible data points for the PNE alone group (33 at baseline, 3, 6, and 12-months). PNE: Pain neuroscience education. CI: Confidence intervals. Model 1 adjusted for patient, follow-up, treatment arm and interaction between follow-up and treatment arm and model 2 further including adjustment for age, sex, and body mass index.
The (−) at these effect sizes indicate that effect was in favor of the PNE alone group.
Fig. 2.
Mean scores for the index knee at baseline and 3-, 6- and 12-months follow-up for the neuromuscular exercise and PNE and the PNE alone groups for the outcomes peak leg extension and maximum muscle strength for the knee extensors and knee flexors. Error bars indicate 95% CI.
The neuromuscular exercise and PNE group experienced a significant within-group improvement for the outcomes maximum muscle strength for the index knee flexors (19.7 N, 95% CI 7.6 to 31.9, P = 0.001) and peak leg extension power for the index knee (26.3 W, 95% CI 4.3 to 48.3, P = 0.019, Table 2). Maximum muscle strength for the index knee extensors did not improve significantly in the neuromuscular exercise and PNE group. In the PNE alone group, no significant improvements were observed from baseline to follow-up in index knee extensor and flexor muscle strength or power (Table 2). The collected data for maximum muscle strength for knee extensors and flexors and peak leg extension power for all assessments are provided in supplementary material 1.
The per protocol analysis revealed similar findings with no between-group differences for any of the outcomes (supplementary material 2).
For the two groups collapsed, the estimates for maximum knee extensor and flexor muscle strength, normalized to percentage of bodyweight was 27.4% for the knee extensors and 17.4% for the knee flexors at 12-months. For the two groups collapsed, the estimate for normalized peak leg extension power was 1.5 W/kg bodyweight at 12-months.
The findings from the multivariable regression analysis can be seen in Table 3. None of the independent variables were significantly associated with overall treatment effect (KOOS4). The R2 values were 0.11, −0.01, and −0.01 for the maximum muscle strength for knee extensor and flexors and peak leg extension power, respectively, at the index knee.
Table 3.
Associations between KOOS4 and maximum muscle strength for knee extensors and flexors and peak leg extension power of the index knee.
| Dependent variables | Independent variables | β | 95% CI | P-value | R2 change |
|---|---|---|---|---|---|
| KOOS4 | Maximum muscle strength knee extensors, index knee | 0.001 | −0.059 to 0.061 | 0.98 | −0.01 |
| Maximum muscle strength knee flexors, index knee | −0.027 | −0.120 to 0.066 | 0.56 | −0.01 | |
| Peak leg extension power, index knee | −0.028 | −0.106 to 0.050 | 0.48 | 0.11 |
KOOS4: Knee injury and Osteoarthritis Outcome Score, including the subscales pain, symptoms, function of daily living and knee-related quality of life. The multivariate regression model was adjusted for age, sex, and body-mass index.
4. Discussions
To our knowledge, this is the first study evaluating muscle strength and leg extension power in patients with chronic pain after TKA. Contrary to our hypothesis, the findings revealed that neuromuscular exercise in combination with PNE did not result in better outcomes in maximum muscle strength or peak leg extension power compared with PNE alone in patients with chronic pain after TKA. Statistically significant within-group improvements in maximum knee flexor muscle strength and peak leg extension power were demonstrated in the neuromuscular exercise and PNE group, whereas no significant improvements were observed in the PNE alone group. No significant associations between changes in muscle strength, leg extension power, and changes in self-reported pain, function and knee-related quality of life were observed. Given the sample size, findings from this study should be considered exploratory.
Though no between-group differences in changes in improvement were observed in the study, we observed significant improvements in the neuromuscular exercise and PNE group for the maximum knee flexor muscle strength and peak leg extension power of the index knee. Although explorative, this could indicate that neuromuscular exercises are useful for improving muscle strength and power in patients with chronic pain after TKA. However, the clinical value of improved knee flexor muscle strength and leg extension power in this population remain uncertain as illustrated by the modest improvements in muscle strength and power and the small effect sizes observed. Exercise frequency (two sessions per week) and type (neuromuscular exercises) might have been insufficient to induce larger gain in muscle strength and power.
The complex mechanisms behind the effect of physical exercise on pain are still a matter of debate [41]. There are conflicting findings concerning the effect of knee extensor muscle strength as a mediator (i.e., to which extent knee extensor muscle strength influences pain) of exercise´s effect on pain in patients with knee osteoarthritis [41,42]. Our exploratory findings of lack of associations between muscle strength and power and self-reported pain, function and knee-related quality of life, further adds to questioning the link between improved muscle strength and power and improvement in patient symptoms. Therefore, other parameters than muscle strength and power are likely to influence self-reported pain, symptoms, function and knee-related quality of life, e.g. psychosocial variables have been proposed as important factors behind chronic pain after TKA [7,43]. Overall, there is a lack of understanding concerning the mechanisms behind the effects from exercise in patients with knee or hip osteoarthritis and this gap in knowledge extends to TKA patients.
We observed an increase in muscle strength and leg extension power from baseline to 6 months in the neuromuscular exercise and PNE group, whereafter the achieved improvements started to decline. Since the structured neuromuscular exercise sessions were performed for the first three months, the decline could be explained by lack of continued exercising at an individual level. No data was available concerning continued exercising for the patients. However, lack of long-term adherence to exercising is a well-known challenge especially when conducted without supervision [44,45].
Reference values for quadriceps muscle strength in TKA patients without chronic pain have been published [19,46]. At 180 days postoperatively, the median quadriceps muscle strength, illustrated as a percentage of bodyweight, for females and males were approx. 21% and 26%, respectively [46]. In the present study, the mean quadriceps muscle strength at 12-months for the combined group of females and males was approx. 27%. Despite the obvious difference in the postsurgical timeframe, the findings indicate that quadriceps muscle strength does not seem to be more impaired compared with the general TKA population. Similarly, leg extension power, reported as normalized to W/kg bodyweight, has been evaluated in patients without chronic pain after TKA. Jakobsen et al. [19] observed a normalized leg extension power of 1.3 Watts/kg. bodyweight in patients 6-months after TKA similar to the present values at 12-months for the combined group of TKA patients with chronic pain. This illustrates that leg extension power seems to be in a similar range in patients with chronic pain after TKA compared with the general TKA population. Although based on explorative analysis, these findings could indicate that muscle strength and leg extension power do not seem to be worse in patients with chronic pain after TKA when compared with the general TKA population.
4.1. Limitations
This study has some limitations. Recruitment was influenced by the Covid pandemic impacting recruitment. We did not reach our intended sample size, impacting the power of the analysis. This could potentially explain the lack of significant between-group differences and lack of association between muscle strength and power and self-reported outcomes of pain, symptoms and knee-related quality of life. Exercises adherence might have influenced our findings with 64% of patients participating in at least 18 out of 24 sessions. Since the feasibility and effect of exercise have not been investigated in patients with chronic pain after TKA, we used neuromuscular exercises as intervention based on a precautionary principle. The neuromuscular exercises were well-tolerated by the patients without any serious adverse events [6]. This could imply that exercises in general could be tolerated by patients with chronic pain after TKA, paving the way for more strenuous exercise activities. Future studies could consider progressive resistance training which has been shown to be effective in improving muscle strength and decrease pain [47,48]. Furthermore, a growing body of evidence demonstrates a substantial inter-individual variability in the response to a standard dose of exercise, highlighting the importance of individualized exercise prescription (i.e., precision exercise medicine) [49]. Individual variability could be influenced by e.g. pain mechanism phenotype, which was not measured in this study.
5. Conclusion
Neuromuscular exercise and PNE did not seem to provide superior improvements in maximum knee extensor and flexor muscle strength and peak leg extension power compared to PNE alone in patients with chronic pain after TKA. Maximum knee flexor muscle strength and peak leg extension power improved significantly in the neuromuscular exercise and PNE group but not in the PNE alone group. This exploratory study observed no associations between changes in muscle strength and leg extension power and changes in self-reported pain, function, and knee-related quality of life. Our findings question the association between improvements in muscle strength and power and pain and function patients with chronic postsurgical pain after TKA. Given the exploratory nature of our study, adequately powered studies and protocols inducing greater gain in muscle strength and power are needed to confirm our findings.
Author contributions
JBL, STS, ML, NHB, TB, LAN, and PM conceptualized and designed the study. All authors were part of the data analysis and interpretation of the data. JBL made the initial draft for the manuscript and all authors provided a critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.
Data sharing
Deidentified participant data and a data dictionary are available from the first author on reasonable request and after approval by the study publication committee. Data cannot be reused unless a collaboration agreement has been signed by both parties.
Role of the funding source
This work was supported by the Danish Rheumatism Association (R168-A5619), the Svend Andersen Foundation and Lions Club Denmark. The funders had no role in designing or conducting the study, data analysis, interpretation of the data or decision to submit the manuscript for publication.
Conflict of interest
STS has received personal fees from Munksgaard, TrustMe-Ed, and Nestlé Health Science, outside the submitted work, and is co-founder of GLA:D®, a not-for profit initiative hosted at University of Southern Denmark aimed at implementing clinical guidelines for osteoarthritis in clinical practice. STS acknowledges to have received funding by a program grant from Region Zealand (Exercise First) and the European Union’s Horizon 2020 research and innovation program under grant agreement No 945377 (ESCAPE). TB has received speaker’s honoraria for talks or expert testimony on the efficacy of exercise therapy to enhance recovery after surgery at meetings or symposia held by biomedical companies (Zimmer Biomet and Novartis) outside the submitted work. TB has received fees for writing textbook chapters (Munksgaard) and for organizing post-graduate education, such as post-graduate courses in clinical exercise physiology (Danish Physical Therapy Organization) or PhD courses on clinical research methodology (University of Copenhagen) outside of the submitted work. All other authors declare no conflict of interest.
Acknowledgements
We thank the participants for their participation in the trial. We thank the Department of Occupational Therapy and Physiotherapy, Aalborg University Hospital, Denmark for administrative and logistic support and the Department of Orthopedic Surgery, Aalborg University Hospital, Denmark for their involvement in recruiting patients.
Handling Editor: Professor H. Madry
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ocarto.2026.100786.
Contributor Information
Jesper Bie Larsen, Email: jbl@hst.aau.dk.
Søren T. Skou, Email: stskou@health.sdu.dk.
Mogens Laursen, Email: mola@rn.dk.
Niels Henrik Bruun, Email: nbru@rn.dk.
Thomas Bandholm, Email: Thomas.Quaade.Bandholm@regionh.dk.
Lars Arendt-Nielsen, Email: lan@hst.aau.dk.
Pascal Madeleine, Email: pm@hst.aau.dk.
Appendix A. Supplementary data
The following are the supplementary data to this article:
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