Blunted Exercise-Induced Hypoalgesia After a 5-Min Low-Intensity Ergometer Exercise in Knee Pain vs Healthy Controls: A Randomized Within-Subject Comparison of BFR vs Non- BFR Warm-Up

Blunted Exercise-Induced Hypoalgesia After a 5-Min Low-Intensity Ergometer Exercise in Knee Pain vs Healthy Controls: A Randomized Within-Subject Comparison of BFR vs Non- BFR Warm-Up | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Blunted Exercise-Induced Hypoalgesia After a 5-Min Low-Intensity Ergometer Exercise in Knee Pain vs Healthy Controls: A Randomized Within-Subject Comparison of BFR vs Non- BFR Warm-Up Yunfeng Zhang, Peng Zhang, Fanjun Qin, Yanjie Hu, Bingbing Pu, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9380597/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 23 You are reading this latest preprint version Abstract Background Exercise-induced hypoalgesia (EIH) is vital for rehabilitation, but its efficacy in patients with knee pain remains controversial. Blood flow restriction (BFR) might augment analgesia through metabolic accumulation. This study aimed to investigate the acute analgesic impact of a low-intensity warm-up with or without BFR and to compare EIH responses between healthy individuals and patients with knee pain. Methods Thirty-eight participants (healthy individuals: n = 26; patients with knee pain: n = 12) were enrolled in a randomized, single-session, within-subject split-body protocol. A 5-minute low-intensity ergometer warm-up was performed. BFR (70% arterial occlusion pressure) was applied to one limb (randomized in healthy, fixed to painful limb in patients), and the contralateral limb was utilized as a simultaneous control. Pressure pain thresholds (PPT) were measured at three peri-patellar sites pre- and post-condition using a Latin Square design. Data were analyzed via Linear Mixed Models. Results A significant main effect of time was observed (p < 0.001), indicating that warm-up significantly increased PPT across all conditions. Crucially, a significant Group × Time interaction (p = 0.001) revealed that the magnitude of exercise-induced hypoalgesia was blunted in the knee pain group (PPT + 2.13 N) compared to the healthy group (PPT + 5.55 N). No significant Group × Condition × Time interaction was found (p = 0.374), suggesting that BFR provided no superior acute analgesia over standard warm-up. Additionally, the main effect of location was identified (p = 0.005), but this did not interact with the condition effect. Conclusions A low-intensity ergometer warm-up effectively induces acute analgesia, but this protective mechanism exhibits significant pathological blunting in patients with knee pain, suggesting that endogenous pain modulation might be impaired. The transient superimposition of BFR did not yield additional acute analgesic benefits. Therefore, rehabilitation interventions for patients with knee pain might require BFR protocols with increased pressure intensities or sustained workloads to unlock potential hypoalgesic benefits. Trial registration Chinese Clinical Trial Registry ChiCTR2300069386 ( https://www.chictr.org.cn/ , registered on 15 March 2023) Exercise-induced hypoalgesia Knee pain Warm-up Pressure pain threshold Blood flow restriction Endogenous pain modulation Figures Figure 1 Figure 2 Introduction Chronic knee pain acts as a significant contributor to global disability, affecting millions of individuals and imposing a substantial burden on healthcare systems [ 1 , 2 ]. Exercise therapy serves as a first-line intervention for knee pain management due to its effects on physical function and pain sensitivity [ 3 , 4 ]. One potential mechanism underlying this benefit is exercise-induced hypoalgesia (EIH), marked by a decrease in overall pain sensitivity and an increase in the pain threshold after a single session of physical activity [ 5 , 6 ]. In healthy individuals, diverse exercise modes, such as aerobic cycling and isometric contractions, can consistently trigger EIH [ 7 , 8 ]. However, in patients suffering from persistent musculoskeletal pain, the efficacy of EIH is frequently and significantly reduced. A growing body of evidence indicates that in patients with chronic knee pain and other chronic pain syndromes, the EIH response is frequently diminished, absent, or in some cases, replaced by a pro-nociceptive response [ 9 – 11 ]. This dysfunctional endogenous pain modulation might originate from central sensitization and impaired conditioned pain modulation (CPM) [ 12 , 13 ]. Therefore, patients with chronic knee pain might not achieve EIH, potentially compromising the compliance and progression of rehabilitation therapy [ 14 ]. Regarding warm-up exercises, they prepare the musculoskeletal system and reduce injury risk during rehabilitation [ 15 ]. Although it is well-known that high-intensity exercise can induce strong EIH by activating high-threshold motor units and descending inhibitory pathways [ 16 , 17 ], due to the mechanical loads on joints, such high-intensity exercise is often contraindicated or difficult for patients with knee pain to tolerate. Therefore, a low-load warm-up strategy might be required to enhance EIH in patients with chronic knee pain. Blood flow restriction (BFR) training has emerged as a powerful approach to tackle this challenge. By applying external pressure on the proximal limb, BFR partially restricts arterial inflow and fully blocks venous outflow, thus creating a local hypoxic environment [ 18 ]. This physiological state accelerates the accumulation of metabolic by-products (lactic acid and protons) at low exercise intensities [ 19 ]. One possible interpretation is that this metabolic stress might stimulate type III and IV muscle afferents, triggering a metabolic reflex that subsequently activates the endogenous opioid and endocannabinoid systems to yield analgesic effects [ 20 , 21 ]. Recent studies have begun to explore the analgesic potential of BFR. Research demonstrates that low-load BFR resistance training can elevate the pressure pain threshold (PPT) in both healthy adults and patients suffering from anterior knee pain [ 22 , 23 ]. However, the literature predominantly focuses on resistance exercise. Data regarding the acute analgesic effects of aerobic BFR warm-ups (cycling or walking) remain inconsistent [ 24 , 25 ]. Moreover, whether a single session of low-intensity BFR cycling might counteract the blunted EIH response in patients with chronic knee pain compared to healthy individuals remains unclear [ 21 ]. To bridge this gap, this study employed a randomized, single-session, within-subject split-body design to investigate the acute effects of a 5-minute low-intensity ergometer warm-up (with or without BFR) on PPT. We aimed to compare the immediate EIH responses between healthy individuals and patients with chronic knee pain. We hypothesized that: (i) a brief low-intensity warm-up would be sufficient to induce a significant EIH across all participants; (ii) patients with knee pain would exhibit a blunted EIH response compared to the healthy control group; and (iii) applying BFR during the warm-up would enhance the acute analgesic effect and potentially normalize the analgesic response in the pain group. Methods Study Design and Setting This study employed a randomized, single-session, within-subject split-body design to evaluate the acute effects of the intervention. This approach allowed for the investigation of acute exercise-induced hypoalgesia while minimizing inter-subject variability by using the contralateral limb as a simultaneous control. The research was predominantly carried out at the Department of Rehabilitation, Shanghai Pudong Hospital (Fudan University Affiliated Pudong Medical Center). Recruitment was facilitated through open-poster advertisements. Participants A total of 38 subjects were recruited from the hospital and the surrounding community via open poster advertisements. This cohort comprised 26 healthy adults (Healthy group) and 12 patients with unilateral knee pain (Pain group). For the Healthy group, inclusion criteria were: (1) aged 18–60 years; (2) free of any current or historical musculoskeletal knee conditions or chronic pain; and (3) provision of written informed consent. For the Pain group, inclusion criteria were: (1) aged 18–60 years; (2) clinical diagnosis of unilateral knee pathology, specifically post-anterior cruciate ligament (ACL) reconstruction, meniscal injury, or knee osteoarthritis; (3) symptom duration of at least 8 weeks; and (4) ability to independently perform low-intensity cycling. To ensure the validity of the pressure pain threshold (PPT) assessment and the absolute safety of the BFR condition, shared exclusion criteria for both groups included: (1) absolute or relative contraindications to BFR (e.g., history of deep vein thrombosis or coagulation disorders); (2) unmanaged hypertension (e.g., resting BP ≥ 140/90 mmHg) or diabetes mellitus with peripheral neuropathy (to prevent neuropathy-related sensory confounders); (3) ongoing anticoagulant therapy; (4) acute knee joint inflammatory flare-ups (e.g., severe swelling, erythema) or a history of recurrent patellar dislocation; (5) use of any analgesic medications (e.g., NSAIDs, opioids) within 48 hours prior to the experiment; (6) intense lower-limb exercise within the preceding 24 hours; (7) current smoking or heavy alcohol consumption; and (8) pregnancy or lactation. To further minimize transient confounding factors, participants were instructed to maintain habitual sleep, avoid caffeine for ≥12 hours, and abstain from physical therapies on the testing day. Despite varying structural diagnoses, all patients shared persistent unilateral knee pain (≥ 8 weeks) and were rigorously screened to exclude acute inflammatory and neuropathic confounders. This rigorous selection provides a representative and homogenous clinical model of chronic nociceptive pain, ideal for evaluating general endogenous pain modulation dysfunction. Split-Body Allocation To investigate the specific effects of BFR while minimizing inter-subject variability, a bilateral comparison model was adopted where one lower limb received the BFR condition, and the contralateral limb served as an internal simultaneous control. For the healthy group, the limb receiving BFR cuff compression was determined by simple randomization (13 on the left side and 13 on the right side). For the pain group, to reflect clinical relevance, the BFR cuff was consistently applied to the affected (painful) lower limb (6 on the left side and 6 on the right side), with the unaffected asymptomatic limb serving as the control. Procedures The experimental protocol consisted of a pre-test, a warm-up condition, and a post-condition assessment, all performed sequentially during a single visit (Figure 1). Prior to the warm-up condition, individualized arterial occlusion pressure (AOP), also referred to as limb occlusion pressure (LOP), was determined. Participants were fitted with wireless pneumatic cuffs (The BFR Cuffs 2.0, SAGA Fitness, QLD, Australia) [26]. A standard regular size cuff (applicable for limb circumferences of 45–64 cm) was applied to the most proximal portion of the designated thigh and secured snugly to accommodate individual limb anthropometry. While the participant rested quietly in a supine position with their leg muscles non-tensed, the AOP was automatically determined utilizing the cuff’s integrated pressure sensors and proprietary algorithms, controlled via the device's companion smartphone application (Bluetooth connection). Following successful calibration, participants completed a 5-minute low-intensity warm-up on a stationary ergometer (Model DLK-NFXLQ-02; Miraclink Medical Technology Co., Ltd., Shenzhen, China). To ensure standardized exercise intensity across all subjects, the device's mechanical resistance was set to level 7, and participants were instructed to maintain a constant pedaling cadence of 60 revolutions per minute (RPM), corresponding to one full alternating leg cycle per second, an additional figure file shows this in more detail [see Additional file 1]. During this time, the pneumatic cuff was inflated to a customized target pressure of 70% of the individual’s calibrated AOP [18], an additional figure file shows this in more detail [see Additional file 1]. Meanwhile, the contralateral limb performed the same exercise without external compression. To ensure the condition was truly low-intensity and accounted for individual fitness differences, we monitored participants’ perceived exertion using the Borg RPE scale (6–20). All participants reported RPE scores of 9–11 (“very light” to “fairly light”), confirming a consistent, low-intensity cardiovascular stimulus without local muscle fatigue [27]. Immediately after the warm-up and cuff deflation, a PPT retest was conducted on both limbs using the same protocol as at baseline to evaluate the immediate analgesic effects of the condition, an additional figure file shows this in more detail [see Additional file 1]. Outcome Measures The PPT was evaluated utilizing a Digital Force Gauge (Model SH-100; Yueqing Handpi Instruments Co., Ltd., Zhejiang, China) equipped with a custom-made probe tip with a contact area of 1 cm², fabricated from high-performance nylon using 3D printing technology. The device features a measurement resolution of 0.01 N and an accuracy of ± 0.5%. Measurements were conducted in "PEAK" mode. In this mode, the LCD screen displays real-time pressure feedback; upon the participant's verbal indication of the first sensation of pain, the examiner immediately retracted the device, and the peak pressure value corresponding to the pain threshold was automatically captured and retained by the instrument. To ensure exact reproducibility, PPT was assessed at three specific anatomical landmarks: (1) Suprapatellar: 10 cm proximal to the superior border of the patella; (2) Infrapatellar (Patellar Tendon): the midpoint of the patellar tendon; and (3) Lateral leg: the proximal one-third of the line connecting the fibular head to the lateral malleolus [28]. To minimize sensitization and potential sequence impacts, the assessment order was randomized at two levels: first, the testing sequence of the two limbs (BFR side vs. Control side) was randomized; second, within each limb, the order of measurements at these three standardized locations was randomized through the utilization of a Latin square design. At each location, pressure was applied perpendicularly to the skin at a constant rate of approximately 1 N/cm²/s until the subject indicated pain. The evaluator maintained this rate using real-time force feedback from the instrument display. The application rate was standardized through extensive pre-experiment pacing training using a metronome to ensure consistent manual pressure. Each location was measured four times consecutively, with a 15-second rest interval between measurements to prevent temporal summation [29]. To minimize inter-rater variability, all PPT assessments were conducted by a single trained evaluator. Although the assessor could not be blinded to limb allocation (due to visible pneumatic cuffs), expectation bias was minimized through multiple safeguards: (1) both assessors and participants were blinded to the study’s primary hypotheses; (2) standardized verbal instructions were used throughout testing; (3) the digital force gauge’s LCD screen was turned away from participants to prevent visual feedback during pain reporting; and (4) a familiarization trial on a remote site (e.g., the forearm) preceded baseline assessment to ensure participants understood the “first sensation of pain” criterion. Safety Monitoring and Termination Criteria Given the vascular and neurological risks of pneumatic compression, participants underwent continuous visual and verbal safety monitoring during the BFR warm-up. The condition was stopped immediately and the cuff fully deflated if any predefined adverse event occurred, such as severe disproportionate pain, intolerable paresthesia (numbness or tingling), skin pallor or cyanosis distal to the cuff, extreme dizziness, or shortness of breath. All such events and associated medical responses were recorded as adverse events. Statistical Analysis We conducted all data preprocessing, statistical modeling, and visualization using custom Python scripts with pandas, statsmodels, scipy, seaborn, and matplotlib. To handle the repeated-measures design’s nested structure, we used Linear Mixed Models (LMMs) for all hypothesis tests. First, an LMM assessed consistency across the four PPT trials (with Trial 1 as reference), confirming that the initial habituation trial could be excluded. The main LMM included Group (healthy vs. pain) as a between-subjects factor, and Condition (BFR vs. control), Time (pre- vs. post-warm-up), and Location (suprapatellar, infrapatellar, lateral leg) as within-subjects factors. We modeled participant-level baseline variability with a random intercept for Subject ID (Variance Components covariance). The primary outcome of interest was the three-way interaction of Group × Condition × Time. Significant main effects or interactions were followed by post-hoc analyses, utilizing simple effect models for repeated measures and Tukey's Honest Significant Difference (HSD) tests for multiple comparisons. The alpha level for statistical significance was set a priori at p < 0.05. Results Participant Characteristics and Safety A total of 38 subjects participated in and completed this study, comprising 26 healthy subjects and 12 subjects with knee pain. Baseline demographic analysis indicated that there were no significant differences between the two groups regarding age (Healthy: 29.50 ± 8.54 years; Pain: 30.75 ± 8.38 years, p = 0.875 ), gender distribution (p = 0.728 ), BMI (22.08 ± 2.88 vs 21.80 ± 3.72 kg/m², p = 0.801 ), or exercise habits (p = 0.509 ). For the Pain group, the average symptom duration was 12.75 ± 10.81 months, and the baseline pain intensity was 3.5 ± 1.2 on the NRS (Table 1). All subjects successfully completed the 5-minute warm-up protocol with simultaneous application of BFR and control conditions on contralateral limbs. No adverse events or exacerbation of knee symptoms were reported, which confirmed the safety and tolerability of the condition in this study population. Preliminary Analysis: Protocol Verification Prior to conducting the main analysis, we carried out a Linear Mixed Model analysis to evaluate the stability of the four consecutive PPT measurements. A significant main effect of repetition was detected. Post-hoc analysis indicated that the first measurement was significantly higher than the second (p = 0.039), third (p = 0.008), and fourth (p = 0.008) measurements (Figure 2A, an additional table file shows this in more detail [see Additional file 1].), implying a potential habituation or apprehension bias during the initial trial. Consequently, to ensure data reliability, we excluded the first measurement. To maximize statistical power, the raw values of the second, third, and fourth measurements were included as nested observations in all subsequent analyses. Crucially, to validate the split-body design within the Knee Pain group (where the BFR condition was fixed to the affected limb), baseline paired comparisons revealed no significant differences in pre-test PPTs between the painful and non-painful contralateral limbs across all measured sites (all p > 0.05). This lack of baseline discrepancy indicates the presence of bilateral central sensitization, thereby ensuring the unaffected limb served as a valid and unbiased simultaneous control. Exercise-Induced Hypoalgesia: Main Effect of Time The linear mixed model analysis revealed a significant main effect of Time across all participants and conditions (z = 5.55, p < 0.001) (An additional table file shows this in more detail [see Additional file 1].). Irrespective of group assignment (either the Healthy group or the Pain group) or condition type (either the BFR or the control condition), the PPT following the 5-minute low-intensity ergometer warm-up was significantly higher than the baseline levels, an additional table file shows this in more detail [see Additional file 1].). This broad increase verified that the exercise protocol effectively induced a systemic pain reduction response, thus validating the presence of exercise-induced hypoalgesia in this study sample. Group Differences in Analgesic Response: The Blunted Exercise-induced Hypoalgesia Effect Crucially, the study detected a significant Group × Time interaction (z = -3.19, p = 0.001), indicating distinct pain modulation patterns between the two cohorts (Figure 2B). Although both groups experienced an elevation in pain thresholds following exercise, there were notable disparities in the magnitude of this enhancement. Post-hoc analysis indicated that the Healthy Group displayed a robust increase in PPT (mean change +5.55 N; 95% CI: 3.79 to 7.31 N), whereas the Knee Pain Group showed a considerably smaller improvement (mean change +2.13 N; 95% CI: 0.15 to 4.11 N). This disparity implies that, in comparison with healthy individuals, the endogenous analgesic mechanisms usually activated by acute exercise appear to be "blunted" or less responsive in patients with knee pain. Effects of Blood Flow Restriction and Measurement Location Regarding the specific effects of condition types, the analysis did not detect a significant main effect of Condition (z = -0.19, p = 0.850) or a Condition × Time interaction (z = 0.11, p = 0.909). Furthermore, no significant Group × Condition × Time interaction (z = 0.89, p = 0.374) was found (Figure 2C). This suggests that the incorporation of BFR (70% Arterial Occlusion Pressure) in the warm-up protocol did not yield statistically superior analgesic effects compared to the control (non-BFR) condition in either group. Additionally, the study found a significant main effect of Location (p = 0.005). Post-hoc Tukey HSD tests revealed that the Lateral Leg (Site 3) exhibited significantly lower absolute PPT values compared to the Suprapatellar (Site 1, p < 0.001) and Infrapatellar (Site 2, p < 0.001) regions (Figure 2D, an additional table file shows this in more detail [see Additional file 1].), likely due to differences in underlying tissue sensitivity. However, this Location factor did not significantly interact with the key outcome measures (Time or Condition), indicating that the exercise-induced hypoalgesia effect was consistent across all measurement sites. Discussion This study aimed to investigate the acute effects of a low-intensity aerobic warm-up with and without BFR on PPT in healthy individuals and patients with knee pain. Our study demonstrated a significant acute EIH effect across all participants after a 5-minute low-intensity ergometer warm-up (significant main effect of time). Traditional exercise physiology has generally posited that triggering robust EIH requires moderate-to-high mechanical loading to adequately activate high-threshold motor units and descending pain inhibitory pathways [6, 17, 30]. However, our finding was in accordance with emerging evidence suggesting that low-load aerobic exercise can effectively serve as a pain pre-conditioning strategy to initiate the endogenous analgesic network [5, 7]. One possible interpretation is that low-intensity cycling provides a safe analgesic window for patients with knee pain intolerant to high mechanical joint loading, establishing a favorable state for subsequent rehabilitation tasks without exacerbating articular cartilage wear [4, 15, 31]. We found a markedly blunted EIH response in the patients with knee pain. The healthy individuals exhibited an increase in post-condition PPT (+5.55 N), whereas the patients with knee pain showed a severely suppressed increment (+2.13 N). This finding reveals a fundamental abnormality in the central pain processing mechanisms of patients with chronic knee pain. This blunting phenomenon provides compelling experimental evidence for the remodeling of central pain modulation networks in patients with chronic or persistent musculoskeletal pain[10, 11, 32]. Prolonged peripheral nociceptive input leads not only to local tissue hypersensitivity but also triggers central nervous system sensitization, thereby impairing the efficiency of conditioned pain modulation [9, 12, 33]. Whereas healthy individuals can effectively release endogenous opioids and activate the descending inhibitory systems of the rostroventral medulla (RVM) and periaqueductal gray (PAG) under exercise-induced physiological stress, this endogenous mechanism appears dysfunctional in patients with knee pain [14, 34, 35]. Collectively, the remodeling of central pain modulation networks might be the reason for this blunting phenomenon, suggesting that clinical rehabilitation must prioritize the restoration of central pain regulatory mechanisms [36]. Regarding the BFR condition, we found that its short-duration application did not confer additional analgesic benefits superior to the standard warm-up. Although extensive literature supports that low-load BFR resistance training can stimulate Group III and IV muscle afferents by accelerating local hypoxia [19-21, 37], the metabolic stress induced by our 5-minute low-intensity aerobic warm-up combined with 70% AOP was likely substantially lower than that generated by traditional BFR protocols [18, 24]. In addition, the mechanical compression and ischemic sensation induced by the BFR tourniquet constitute a heterotopic noxious stimulus. In healthy individuals, this stimulus triggers a pain-inhibits-pain response [13]; however, in patients with knee pain with impaired CPM, this ischemic discomfort translates into a competing nociceptive input, thereby neutralizing potential metabolic analgesic gains [25, 38, 39]. Methodologically, our study demonstrated extreme instability and significant elevation in the first recorded value among the four consecutive PPT measurements. This initial measurement error can be attributed to novelty anxiety regarding the algometer probe's compression, muscle guarding, or hypervigilance toward expected pain [40, 41]. As measurements were repeated, subjects habituated to the mechanical stimulus. Therefore, the mean of the subsequent three trials accurately reflects the stable baseline PPT, suggesting that future clinical pain studies should routinely discard the first PPT measurement to minimize the confounding influence of psychological expectations [42]. Spatial analysis of the three peri-patellar measurement sites revealed a significant main effect of location without interaction with the conditions, indicating natural PPT discrepancies across different anatomical sites [28, 43]. However, the consistent magnitude of analgesia across these distinct regions further supports that EIH is primarily a regional analgesic mechanism mediated by the central nervous system [7, 44]. Finally, several limitations of this study should be mentioned. (i) The sample size of the patients with knee pain was relatively small and encompassed a heterogeneous range of pathological states, which precluded sub-group analyses based on specific etiologies. (ii) The cross-sectional design evaluated only the acute effects of a single BFR condition. (iii) Due to the palpable nature of cuff inflation, true blinding to the BFR condition was unfeasible, which might introduce expectation bias, although multiple safeguards were employed during measurements. Future longitudinal randomized controlled trials with larger sample sizes are required to investigate whether chronic BFR aerobic training can induce long-term neuroplastic adaptations in patients with knee pain [8, 21]. In conclusion, our findings revealed that a low-intensity aerobic warm-up contributes to acute analgesia, but this endogenous protective mechanism exhibits significant pathological blunting in patients with knee pain. The transient superimposition of BFR did not yield additional acute analgesic benefits. Rehabilitation interventions for patients with knee pain require the exploration of BFR protocols with higher metabolic loads or longer durations to unlock its full analgesic potential. Conclusion Our study demonstrated that a 5-minute low-intensity cycling warm-up effectively elicited immediate EIH. However, this endogenous analgesic response was significantly blunted in patients with knee pain, reflecting a potential impairment in central pain modulation. Regarding the BFR condition, the concurrent application of short-duration occlusion did not yield additive hypoalgesic benefits. One possible interpretation is that higher metabolic stress or longer occlusion durations might be required to trigger BFR-mediated analgesia. Methodologically, the initial PPT measurement should be excluded in future clinical assessments to mitigate novelty-induced sensitization and ensure data reliability. Collectively, although low-load active warm-ups remain clinically valuable for pain management, future research should optimize BFR protocols to effectively address the blunted EIH response in patients with knee pain. Abbreviations EIH Exercise-Induced Hypoalgesia BFR Blood Flow Restriction PPT Pressure Pain Threshold AOP Arterial Occlusion Pressure LMM Linear Mixed Model CPM Conditioned Pain Modulation BMI Body Mass Index NRS Numeric Rating Scale SD Standard Deviation RVM Rostroventral Medulla PAG Periaqueductal Gray Declarations Ethics approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Shanghai Pudong Hospital (Approval No.2023-WZ-03). All participants provided written informed consent. Consent for publication: We confirm that all data and photographs were obtained with the subjects' informed consent. They voluntarily agreed to their use for publication, and the consent records are available for verification. Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: This work was supported by the National Natural Science Foundation of China (82102665) and the Shanghai Sailing Program (21YF1404600). Authors ' contributions: HW and QL conceived and designed the study. YFZ, PZ, and FQ performed the experiments and collected the data. BP, HQ, and XX were responsible for data curation and statistical analysis. ZB and YC assisted in the investigation and methodology. YFZ and PZ drafted the original manuscript. LC and YH reviewed and edited the manuscript. HW supervised the entire project. All authors have read and agreed to the final manuscript. Acknowledgements: We would like to express our gratitude to all the volunteers who participated in this study. We would like to express our sincere gratitude to Shuqin Liu, Ziyi Zhou, and Xiaoyue Zhai for their efforts in data collation and photo shooting. Declaration of AI Usage: During the preparation of this work, the authors utilized artificial intelligence tools solely for language polishing and grammatical correction to enhance readability. No AI tools were used to generate scientific content or data. The authors have reviewed the final text and take full responsibility for the content of this publication. 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Korakakis V, Whiteley R, Giakas G: Low load resistance training with blood flow restriction decreases anterior knee pain more than resistance training alone. A pilot randomised controlled trial . Physical therapy in sport : official journal of the Association of Chartered Physiotherapists in Sports Medicine 2018, 34 :121-128. Ogrezeanu DC, López-Bueno L, Sanchís-Sánchez E, Suso-Martí L, López-Bueno R, Núñez-Cortés R, Cruz-Montecinos C, Pérez-Alenda S, Casaña J, Gargallo P et al : Exercise-induced hypoalgesia with end-stage knee osteoarthritis during different blood flow restriction levels: Sham-controlled crossover study . PM & R : the journal of injury, function, and rehabilitation 2023, 15 (12):1565-1573. Schleip R, Herzer Santana J, Egner C, Brandl A, Overmann L: Acute Effects of Low-Intensity Blood-Flow-Restricted Walking on Pain Sensitivity, Joint Range of Motion, and Myofascial Stiffness in Healthy Adults . Journal of clinical medicine 2026, 15 (3). Swain P, McEwen J, Lai T, Hughes L: Tourniquet cuff pressure during blood flow restriction exercise . Frontiers in sports and active living 2025, 7 :1582387. Ding W, You T, Gona PN, Milliken LA: Validity and reliability of a Chinese rating of perceived exertion scale in young Mandarin speaking adults . Sports medicine and health science 2020, 2 (3):153-158. Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T: Sensitization in patients with painful knee osteoarthritis . Pain 2010, 149 (3):573-581. Mailloux C, Beaulieu LD, Wideman TH, Massé-Alarie H: Within-session test-retest reliability of pressure pain threshold and mechanical temporal summation in healthy subjects . PLoS One 2021, 16 (1):e0245278. Hoffman MD, Shepanski MA, Ruble SB, Valic Z, Buckwalter JB, Clifford PS: Intensity and duration threshold for aerobic exercise-induced analgesia to pressure pain . Archives of physical medicine and rehabilitation 2004, 85 (7):1183-1187. Sluka KA, O'Donnell JM, Danielson J, Rasmussen LA: Regular physical activity prevents development of chronic pain and activation of central neurons . Journal of applied physiology (Bethesda, Md : 1985) 2013, 114 (6):725-733. Woolf CJ: Central sensitization: implications for the diagnosis and treatment of pain . Pain 2011, 152 (3 Suppl):S2-s15. Lewis GN, Rice DA, McNair PJ: Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis . The journal of pain 2012, 13 (10):936-944. Ossipov MH, Morimura K, Porreca F: Descending pain modulation and chronification of pain . Current opinion in supportive and palliative care 2014, 8 (2):143-151. Thorén P, Floras JS, Hoffmann P, Seals DR: Endorphins and exercise: physiological mechanisms and clinical implications . Medicine and science in sports and exercise 1990, 22 (4):417-428. Nijs J, Daenen L, Cras P, Struyf F, Roussel N, Oostendorp RA: Nociception affects motor output: a review on sensory-motor interaction with focus on clinical implications . The Clinical journal of pain 2012, 28 (2):175-181. Scott BR, Loenneke JP, Slattery KM, Dascombe BJ: Blood flow restricted exercise for athletes: A review of available evidence . Journal of science and medicine in sport 2016, 19 (5):360-367. Hughes L, Patterson SD: The effect of blood flow restriction exercise on exercise-induced hypoalgesia and endogenous opioid and endocannabinoid mechanisms of pain modulation . Journal of applied physiology (Bethesda, Md : 1985) 2020, 128 (4):914-924. Ramaswamy S, Wodehouse T: Conditioned pain modulation-A comprehensive review . Neurophysiologie clinique = Clinical neurophysiology 2021, 51 (3):197-208. Walton DM, Macdermid JC, Nielson W, Teasell RW, Chiasson M, Brown L: Reliability, standard error, and minimum detectable change of clinical pressure pain threshold testing in people with and without acute neck pain . The Journal of orthopaedic and sports physical therapy 2011, 41 (9):644-650. Rhudy JL, Meagher MW: Fear and anxiety: divergent effects on human pain thresholds . Pain 2000, 84 (1):65-75. Mutlu EK, Ozdincler AR: Reliability and responsiveness of algometry for measuring pressure pain threshold in patients with knee osteoarthritis . Journal of physical therapy science 2015, 27 (6):1961-1965. Fonkoué L, Behets C, Kouassi JK, Coyette M, Detrembleur C, Thienpont E, Cornu O: Distribution of sensory nerves supplying the knee joint capsule and implications for genicular blockade and radiofrequency ablation: an anatomical study . Surgical and radiologic anatomy : SRA 2019, 41 (12):1461-1471. Courtney CA, Steffen AD, Fernández-de-Las-Peñas C, Kim J, Chmell SJ: Joint Mobilization Enhances Mechanisms of Conditioned Pain Modulation in Individuals With Osteoarthritis of the Knee . The Journal of orthopaedic and sports physical therapy 2016, 46 (3):168-176. Table Table 1. Baseline Characteristics Characteristic Healthy Group (n = 26) Knee Pain Group (n = 12) p -value Demographics Age (years) 29.50±8.54 30.75±8.38 0.875 Gender (Male / Female), n 15 / 11 8 / 4 0.728 BMI (kg/m²) 22.08±2.88 21.80±3.72 0.801 Education (years) 16.00±2.56 15.33±2.19 0.843 Exercise Habits (hours/week) 1.79±2.38 2.04±2.98 0.509 Condition Parameters Arterial Occlusion Pressure (mmHg) 164.73±28.83 159.33±23.95 0.576 BFR Side (Left / Right), n 13 / 13 6 / 6 1.000 Clinical Characteristics (Pain Group only) Symptom Duration (months) — 12.75±10.81 — Baseline Pain Intensity (NRS, 0-10) — 3.5±1.2 — Pathology Type , n (%) Post-operative ACL Reconstruction — 5 (41.7%) — Meniscal Injury — 3 (25.0%) — Knee Osteoarthritis — 4 (33.3%) — Note: Data are presented as mean ± standard deviation (SD) for continuous variables and frequency (n) for categorical variables. p -values were calculated using independent t-tests for continuous variables and Chi-square tests for categorical variables. BMI: Body Mass Index; NRS: Numeric Rating Scales; ACL: Anterior Cruciate Ligament. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9380597","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":634015765,"identity":"11e69bbc-6918-49e7-9e4a-cf0376b421da","order_by":0,"name":"Yunfeng Zhang","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yunfeng","middleName":"","lastName":"Zhang","suffix":""},{"id":634015766,"identity":"d6ccded7-f161-47fd-b8d3-1a1aa55d04cd","order_by":1,"name":"Peng Zhang","email":"","orcid":"","institution":"Fifth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Zhang","suffix":""},{"id":634015767,"identity":"cc8c858a-fecf-4d31-9ce7-e0f2632ac21a","order_by":2,"name":"Fanjun Qin","email":"","orcid":"","institution":"Shanghai Pudong Hospital, Fudan University Affiliated Pudong Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Fanjun","middleName":"","lastName":"Qin","suffix":""},{"id":634015768,"identity":"c4f84893-cdb4-405d-964c-2e7c76a5a84f","order_by":3,"name":"Yanjie Hu","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanjie","middleName":"","lastName":"Hu","suffix":""},{"id":634015769,"identity":"803e48e8-6b00-497b-9854-9320ff45e849","order_by":4,"name":"Bingbing Pu","email":"","orcid":"","institution":"Shanghai Pudong Hospital, Fudan University Affiliated Pudong Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Bingbing","middleName":"","lastName":"Pu","suffix":""},{"id":634015770,"identity":"180f0f15-1f86-4402-b7cc-8885dcae4204","order_by":5,"name":"Haozhe Qu","email":"","orcid":"","institution":"Shanghai Pudong Hospital, Fudan University Affiliated Pudong Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Haozhe","middleName":"","lastName":"Qu","suffix":""},{"id":634015771,"identity":"965adf0a-c1d3-4396-b491-d70da491f5bd","order_by":6,"name":"Xiaodi Xia","email":"","orcid":"","institution":"Shanghai Hebin Rehabilitation Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaodi","middleName":"","lastName":"Xia","suffix":""},{"id":634015772,"identity":"b63c8e6e-d025-47da-84f0-407fabe2121e","order_by":7,"name":"Zhaodong Bi","email":"","orcid":"","institution":"Huashan 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ziheng","middleName":"","lastName":"Mao","suffix":""},{"id":634015778,"identity":"e6f2daf6-f6b2-4070-a54d-7499cf870dc4","order_by":11,"name":"Yanzheng Zhang","email":"","orcid":"","institution":"Shanghai Hebin Rehabilitation Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanzheng","middleName":"","lastName":"Zhang","suffix":""},{"id":634015779,"identity":"42dd0c50-f6fd-4c67-95f1-35db2b2a4e83","order_by":12,"name":"Qiang Liu","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Liu","suffix":""},{"id":634015782,"identity":"6c08f7e7-750b-40c9-8414-e12842a80ffa","order_by":13,"name":"Hewei Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYJACZiCWY29gMABxGBuI1WLMc4BULYk9RGsxOH728OuCisPpPRLJGz8XMNjIbjjA/OwBXi1n8tKsZ5w5nNsjkVYsPYMhzXjDATZzA3xazA7kmBnztt3O3S+RYyDNw3A4ccMBHjYJvFrOvwFq+Xc7nUcix/g3D8N/IrTcyDF+zNtwOwGoxQxoywHCWuxvvDFj5jn237CH51mZNY9BsvHMw2xmeLVI9ucYf+apSZPnYU/efJunwk6273jzM7xagADZGaCgYiagHqTkA2E1o2AUjIJRMKIBAElnR4CNIOEdAAAAAElFTkSuQmCC","orcid":"","institution":"Huashan Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hewei","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-04-10 14:23:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9380597/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9380597/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108629921,"identity":"3c2c0117-c189-4c20-8e09-9714e96961cb","added_by":"auto","created_at":"2026-05-06 16:30:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5724771,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of the experimental design and study protocol. \u003c/strong\u003eThe study employed a single-session, acute, within-subject split-body experimental design involving 38 participants (26 healthy individuals and 12 patients with knee pain). (Stage 1: Recruitment) Participants were recruited and categorized into a Healthy Group (n = 26) and a Knee Pain Group (n = 12). (Stage 2: Baseline Assessment) General demographic and clinical data were collected. (Stage 3: Pre-test) Baseline PPT was measured at three sites (Suprapatellar, Infrapatellar, Lateral leg). At each site, four consecutive measurements were taken (15s interval). The measurement order of the three sites was randomized using a Latin square design. (Stage 4: Condition) Participants performed a 5-minute low-intensity cycling warm-up using a split-body design. In the Healthy Group, BFR was applied to a randomized limb; in the Knee Pain Group, BFR was applied to the painful limb. (Stage 5: Post-test) Immediately after the condition, PPT measurements were repeated using the same protocol as Stage 3. (Stage 6: Data Analysis) Statistical analysis was performed using a Linear Mixed Model to evaluate the effects of Group, Time, and Treatment. Abbreviations: BFR, Blood Flow Restriction; PPT, Pressure Pain Threshold; Arterial Occlusion Pressure.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9380597/v1/7f199febea362951f4d3f4d7.png"},{"id":108805679,"identity":"79a9f3fe-5a36-4b47-ad9d-1107536e93aa","added_by":"auto","created_at":"2026-05-08 15:26:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3071267,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalysis of Pressure Pain Threshold responses\u003c/strong\u003e. (A) Verification of the measurement protocol: The first repetition of PPT measurement was significantly higher than the subsequent second (p = 0.039), third (p = 0.008), and fourth (p = 0.008) repetitions across all participants, justifying the exclusion of the first measure. (B) Exercise-Induced Hypoalgesia response: A significant Group × Time interaction (p = 0.001) was observed. While both groups exhibited increased PPTs post-exercise, the magnitude of exercise-induced hypoalgesia was notably larger in the Healthy Group (+5.55 N) compared to the Knee Pain Group (+2.13 N), indicating a blunted hypoalgesic response in patients. (C) Treatment effect: There was no significant Treatment × Time interaction (p = 0.909), suggesting that adding BFR to the warm-up did not induce superior analgesia compared to the Control condition. (D) Location effect: A significant main effect of location was found (p = 0.005), with the Lateral Leg site demonstrating significantly lower absolute PPT values compared to the Suprapatellar and Infrapatellar sites.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9380597/v1/a514d07e641dfff5c4513999.png"},{"id":108809856,"identity":"4886b32d-0edf-455e-bb1d-b6b01420df4b","added_by":"auto","created_at":"2026-05-08 15:55:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10121466,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9380597/v1/87e6ec1f-491d-45ff-8851-af07b9136bd3.pdf"},{"id":108805363,"identity":"5ac19c00-0f20-481a-b53f-06613dd6273c","added_by":"auto","created_at":"2026-05-08 15:25:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":3544209,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9380597/v1/f025d01564682cb08667670f.docx"},{"id":108629923,"identity":"3ccd4676-d9ee-49d1-9440-1d918ac5669a","added_by":"auto","created_at":"2026-05-06 16:30:33","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":98049,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2025editablechecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9380597/v1/ecad17a19ce782be519b9ce4.pdf"},{"id":108805197,"identity":"58f132fc-1315-4775-b463-49aeab9fbda9","added_by":"auto","created_at":"2026-05-08 15:25:10","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":3260003,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9380597/v1/7144ae5f05ce1f0f83347c89.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Blunted Exercise-Induced Hypoalgesia After a 5-Min Low-Intensity Ergometer Exercise in Knee Pain vs Healthy Controls: A Randomized Within-Subject Comparison of BFR vs Non- BFR Warm-Up","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic knee pain acts as a significant contributor to global disability, affecting millions of individuals and imposing a substantial burden on healthcare systems [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Exercise therapy serves as a first-line intervention for knee pain management due to its effects on physical function and pain sensitivity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. One potential mechanism underlying this benefit is exercise-induced hypoalgesia (EIH), marked by a decrease in overall pain sensitivity and an increase in the pain threshold after a single session of physical activity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In healthy individuals, diverse exercise modes, such as aerobic cycling and isometric contractions, can consistently trigger EIH [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, in patients suffering from persistent musculoskeletal pain, the efficacy of EIH is frequently and significantly reduced. A growing body of evidence indicates that in patients with chronic knee pain and other chronic pain syndromes, the EIH response is frequently diminished, absent, or in some cases, replaced by a pro-nociceptive response [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This dysfunctional endogenous pain modulation might originate from central sensitization and impaired conditioned pain modulation (CPM) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, patients with chronic knee pain might not achieve EIH, potentially compromising the compliance and progression of rehabilitation therapy [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding warm-up exercises, they prepare the musculoskeletal system and reduce injury risk during rehabilitation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although it is well-known that high-intensity exercise can induce strong EIH by activating high-threshold motor units and descending inhibitory pathways [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], due to the mechanical loads on joints, such high-intensity exercise is often contraindicated or difficult for patients with knee pain to tolerate. Therefore, a low-load warm-up strategy might be required to enhance EIH in patients with chronic knee pain.\u003c/p\u003e \u003cp\u003eBlood flow restriction (BFR) training has emerged as a powerful approach to tackle this challenge. By applying external pressure on the proximal limb, BFR partially restricts arterial inflow and fully blocks venous outflow, thus creating a local hypoxic environment [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This physiological state accelerates the accumulation of metabolic by-products (lactic acid and protons) at low exercise intensities [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. One possible interpretation is that this metabolic stress might stimulate type III and IV muscle afferents, triggering a metabolic reflex that subsequently activates the endogenous opioid and endocannabinoid systems to yield analgesic effects [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies have begun to explore the analgesic potential of BFR. Research demonstrates that low-load BFR resistance training can elevate the pressure pain threshold (PPT) in both healthy adults and patients suffering from anterior knee pain [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, the literature predominantly focuses on resistance exercise. Data regarding the acute analgesic effects of aerobic BFR warm-ups (cycling or walking) remain inconsistent [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Moreover, whether a single session of low-intensity BFR cycling might counteract the blunted EIH response in patients with chronic knee pain compared to healthy individuals remains unclear [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo bridge this gap, this study employed a randomized, single-session, within-subject split-body design to investigate the acute effects of a 5-minute low-intensity ergometer warm-up (with or without BFR) on PPT. We aimed to compare the immediate EIH responses between healthy individuals and patients with chronic knee pain. We hypothesized that: (i) a brief low-intensity warm-up would be sufficient to induce a significant EIH across all participants; (ii) patients with knee pain would exhibit a blunted EIH response compared to the healthy control group; and (iii) applying BFR during the warm-up would enhance the acute analgesic effect and potentially normalize the analgesic response in the pain group.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study employed a randomized, single-session, within-subject split-body design to evaluate the acute effects of the intervention. This approach allowed for the investigation of acute exercise-induced hypoalgesia while minimizing inter-subject variability by using the contralateral limb as a simultaneous control. The research was predominantly carried out at the Department of Rehabilitation, Shanghai Pudong Hospital (Fudan University Affiliated Pudong Medical Center). Recruitment was facilitated through open-poster advertisements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 38 subjects were recruited from the hospital and the surrounding community via open poster advertisements. This cohort comprised 26 healthy adults (Healthy group) and 12 patients with unilateral knee pain (Pain group).\u003c/p\u003e\n\u003cp\u003eFor the Healthy group, inclusion criteria were: (1) aged 18\u0026ndash;60 years; (2) free of any current or historical musculoskeletal knee conditions or chronic pain; and (3) provision of written informed consent. For the Pain group, inclusion criteria were: (1) aged 18\u0026ndash;60 years; (2) clinical diagnosis of unilateral knee pathology, specifically post-anterior cruciate ligament (ACL) reconstruction, meniscal injury, or knee osteoarthritis; (3) symptom duration of at least 8 weeks; and (4) ability to independently perform low-intensity cycling. To ensure the validity of the pressure pain threshold (PPT) assessment and the absolute safety of the BFR condition, shared exclusion criteria for both groups included: (1) absolute or relative contraindications to BFR (e.g., history of deep vein thrombosis or coagulation disorders); (2) unmanaged hypertension (e.g., resting BP \u0026ge; 140/90 mmHg) or diabetes mellitus with peripheral neuropathy (to prevent neuropathy-related sensory confounders); (3) ongoing anticoagulant therapy; (4) acute knee joint inflammatory flare-ups (e.g., severe swelling, erythema) or a history of recurrent patellar dislocation; (5) use of any analgesic medications (e.g., NSAIDs, opioids) within 48 hours prior to the experiment; (6) intense lower-limb exercise within the preceding 24 hours; (7) current smoking or heavy alcohol consumption; and (8) pregnancy or lactation. To further minimize transient confounding factors, participants were instructed to maintain habitual sleep, avoid caffeine for \u0026ge;12 hours, and abstain from physical therapies on the testing day. Despite varying structural diagnoses, all patients shared persistent unilateral knee pain (\u0026ge; 8 weeks) and were rigorously screened to exclude acute inflammatory and neuropathic confounders. This rigorous selection provides a representative and homogenous clinical model of chronic nociceptive pain, ideal for evaluating general endogenous pain modulation dysfunction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSplit-Body Allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the specific effects of BFR while minimizing inter-subject variability, a bilateral comparison model was adopted where one lower limb received the BFR condition, and the contralateral limb served as an internal simultaneous control. For the healthy group, the limb receiving BFR cuff compression was determined by simple randomization (13 on the left side and 13 on the right side). For the pain group, to reflect clinical relevance, the BFR cuff was consistently applied to the affected (painful) lower limb (6 on the left side and 6 on the right side), with the unaffected asymptomatic limb serving as the control.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe experimental protocol consisted of a pre-test, a warm-up condition, and a post-condition assessment, all performed sequentially during a single visit (Figure 1). Prior to the warm-up condition, individualized arterial occlusion pressure (AOP), also referred to as limb occlusion pressure (LOP), was determined. Participants were fitted with wireless pneumatic cuffs (The BFR Cuffs 2.0, SAGA Fitness, QLD, Australia) [26]. A standard regular size cuff (applicable for limb circumferences of 45\u0026ndash;64 cm) was applied to the most proximal portion of the designated thigh and secured snugly to accommodate individual limb anthropometry. While the participant rested quietly in a supine position with their leg muscles non-tensed, the AOP was automatically determined utilizing the cuff\u0026rsquo;s integrated pressure sensors and proprietary algorithms, controlled via the device\u0026apos;s companion smartphone application (Bluetooth connection). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollowing successful calibration, participants completed a 5-minute low-intensity warm-up on a stationary ergometer (Model DLK-NFXLQ-02; Miraclink Medical Technology Co., Ltd., Shenzhen, China). To ensure standardized exercise intensity across all subjects, the device\u0026apos;s mechanical resistance was set to level 7, and participants were instructed to maintain a constant pedaling cadence of 60 revolutions per minute (RPM), corresponding to one full alternating leg cycle per second, an additional figure file shows this in more detail [see Additional file 1]. During this time, the pneumatic cuff was inflated to a customized target pressure of 70% of the individual\u0026rsquo;s calibrated AOP [18], an additional figure file shows this in more detail [see Additional file 1]. Meanwhile, the contralateral limb performed the same exercise without external compression. To ensure the condition was truly low-intensity and accounted for individual fitness differences, we monitored participants\u0026rsquo; perceived exertion using the Borg RPE scale (6\u0026ndash;20). All participants reported RPE scores of 9\u0026ndash;11 (\u0026ldquo;very light\u0026rdquo; to \u0026ldquo;fairly light\u0026rdquo;), confirming a consistent, low-intensity cardiovascular stimulus without local muscle fatigue [27]. Immediately after the warm-up and cuff deflation, a PPT retest was conducted on both limbs using the same protocol as at baseline to evaluate the immediate analgesic effects of the condition, an additional figure file shows this in more detail [see Additional file 1].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome Measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PPT was evaluated utilizing a Digital Force Gauge (Model SH-100; Yueqing Handpi Instruments Co., Ltd., Zhejiang, China) equipped with a custom-made probe tip with a contact area of 1 cm\u0026sup2;, fabricated from high-performance nylon using 3D printing technology. The device features a measurement resolution of 0.01 N and an accuracy of \u0026plusmn; 0.5%. Measurements were conducted in \u0026quot;PEAK\u0026quot; mode. In this mode, the LCD screen displays real-time pressure feedback; upon the participant\u0026apos;s verbal indication of the first sensation of pain, the examiner immediately retracted the device, and the peak pressure value corresponding to the pain threshold was automatically captured and retained by the instrument.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo ensure exact reproducibility, PPT was assessed at three specific anatomical landmarks: (1) Suprapatellar: 10 cm proximal to the superior border of the patella; (2) Infrapatellar (Patellar Tendon): the midpoint of the patellar tendon; and (3) Lateral leg: the proximal one-third of the line connecting the fibular head to the lateral malleolus [28]. To minimize sensitization and potential sequence impacts, the assessment order was randomized at two levels: first, the testing sequence of the two limbs (BFR side vs. Control side) was randomized; second, within each limb, the order of measurements at these three standardized locations was randomized through the utilization of a Latin square design. At each location, pressure was applied perpendicularly to the skin at a constant rate of approximately 1 N/cm\u0026sup2;/s until the subject indicated pain. The evaluator maintained this rate using real-time force feedback from the instrument display. The application rate was standardized through extensive pre-experiment pacing training using a metronome to ensure consistent manual pressure. Each location was measured four times consecutively, with a 15-second rest interval between measurements to prevent temporal summation [29].\u003c/p\u003e\n\u003cp\u003eTo minimize inter-rater variability, all PPT assessments were conducted by a single trained evaluator. Although the assessor could not be blinded to limb allocation (due to visible pneumatic cuffs), expectation bias was minimized through multiple safeguards: (1) both assessors and participants were blinded to the study\u0026rsquo;s primary hypotheses; (2) standardized verbal instructions were used throughout testing; (3) the digital force gauge\u0026rsquo;s LCD screen was turned away from participants to prevent visual feedback during pain reporting; and (4) a familiarization trial on a remote site (e.g., the forearm) preceded baseline assessment to ensure participants understood the \u0026ldquo;first sensation of pain\u0026rdquo; criterion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Monitoring and Termination Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven the vascular and neurological risks of pneumatic compression, participants underwent continuous visual and verbal safety monitoring during the BFR warm-up. The condition was stopped immediately and the cuff fully deflated if any predefined adverse event occurred, such as severe disproportionate pain, intolerable paresthesia (numbness or tingling), skin pallor or cyanosis distal to the cuff, extreme dizziness, or shortness of breath. All such events and associated medical responses were recorded as adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted all data preprocessing, statistical modeling, and visualization using custom Python scripts with pandas, statsmodels, scipy, seaborn, and matplotlib. To handle the repeated-measures design\u0026rsquo;s nested structure, we used Linear Mixed Models (LMMs) for all hypothesis tests. First, an LMM assessed consistency across the four PPT trials (with Trial 1 as reference), confirming that the initial habituation trial could be excluded. The main LMM included Group (healthy vs. pain) as a between-subjects factor, and Condition (BFR vs. control), Time (pre- vs. post-warm-up), and Location (suprapatellar, infrapatellar, lateral leg) as within-subjects factors. We modeled participant-level baseline variability with a random intercept for Subject ID (Variance Components covariance). The primary outcome of interest was the three-way interaction of Group \u0026times; Condition \u0026times; Time. Significant main effects or interactions were followed by post-hoc analyses, utilizing simple effect models for repeated measures and Tukey\u0026apos;s Honest Significant Difference (HSD) tests for multiple comparisons. The alpha level for statistical significance was set a priori at p \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eParticipant Characteristics and Safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 38 subjects participated in and completed this study, comprising 26 healthy subjects and 12 subjects with knee pain. Baseline demographic analysis indicated that there were no significant differences between the two groups regarding age (Healthy: 29.50 \u0026plusmn; 8.54 years; Pain: 30.75 \u0026plusmn; 8.38 years, p = 0.875 ), gender distribution (p = 0.728 ), BMI (22.08 \u0026plusmn; 2.88 vs 21.80 \u0026plusmn; 3.72 kg/m\u0026sup2;, p = 0.801 ), or exercise habits (p = 0.509 ). For the Pain group, the average symptom duration was 12.75 \u0026plusmn; 10.81 months, and the baseline pain intensity was 3.5 \u0026plusmn; 1.2 on the NRS (Table 1). All subjects successfully completed the 5-minute warm-up protocol with simultaneous application of BFR and control conditions on contralateral limbs. No adverse events or exacerbation of knee symptoms were reported, which confirmed the safety and tolerability of the condition in this study population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreliminary Analysis: Protocol Verification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrior to conducting the main analysis, we carried out a Linear Mixed Model analysis to evaluate the stability of the four consecutive PPT measurements. A significant main effect of repetition was detected. Post-hoc analysis indicated that the first measurement was significantly higher than the second (p = 0.039), third (p = 0.008), and fourth (p = 0.008) measurements (Figure 2A, an additional table file shows this in more detail [see Additional file 1].), implying a potential habituation or apprehension bias during the initial trial. Consequently, to ensure data reliability, we excluded the first measurement. To maximize statistical power, the raw values of the second, third, and fourth measurements were included as nested observations in all subsequent analyses. Crucially, to validate the split-body design within the Knee Pain group (where the BFR condition was fixed to the affected limb), baseline paired comparisons revealed no significant differences in pre-test PPTs between the painful and non-painful contralateral limbs across all measured sites (all p \u0026gt; 0.05). This lack of baseline discrepancy indicates the presence of bilateral central sensitization, thereby ensuring the unaffected limb served as a valid and unbiased simultaneous control.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExercise-Induced Hypoalgesia: Main Effect of Time\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe linear mixed model analysis revealed a significant main effect of Time across all participants and conditions (z = 5.55, p \u0026lt; 0.001) (An additional table file shows this in more detail [see Additional file 1].). Irrespective of group assignment (either the Healthy group or the Pain group) or condition type (either the BFR or the control condition), the PPT following the 5-minute low-intensity ergometer warm-up was significantly higher than the baseline levels, an additional table file shows this in more detail [see Additional file 1].). This broad increase verified that the exercise protocol effectively induced a systemic pain reduction response, thus validating the presence of exercise-induced hypoalgesia in this study sample.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroup Differences in Analgesic Response: The Blunted Exercise-induced Hypoalgesia Effect\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCrucially, the study detected a significant Group \u0026times; Time interaction (z = -3.19, p = 0.001), indicating distinct pain modulation patterns between the two cohorts (Figure 2B). Although both groups experienced an elevation in pain thresholds following exercise, there were notable disparities in the magnitude of this enhancement. Post-hoc analysis indicated that the Healthy Group displayed a robust increase in PPT (mean change +5.55 N; 95% CI: 3.79 to 7.31 N), whereas the Knee Pain Group showed a considerably smaller improvement (mean change +2.13 N; 95% CI: 0.15 to 4.11 N). This disparity implies that, in comparison with healthy individuals, the endogenous analgesic mechanisms usually activated by acute exercise appear to be \u0026quot;blunted\u0026quot; or less responsive in patients with knee pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffects of Blood Flow Restriction and Measurement Location\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding the specific effects of condition types, the analysis did not detect a significant main effect of Condition (z = -0.19, p = 0.850) or a Condition \u0026times; Time interaction (z = 0.11, p = 0.909). Furthermore, no significant Group \u0026times; Condition \u0026times; Time interaction (z = 0.89, p = 0.374) was found (Figure 2C). This suggests that the incorporation of BFR (70% Arterial Occlusion Pressure) in the warm-up protocol did not yield statistically superior analgesic effects compared to the control (non-BFR) condition in either group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, the study found a significant main effect of Location (p = 0.005). Post-hoc Tukey HSD tests revealed that the Lateral Leg (Site 3) exhibited significantly lower absolute PPT values compared to the Suprapatellar (Site 1, p \u0026lt; 0.001) and Infrapatellar (Site 2, p \u0026lt; 0.001) regions (Figure 2D, an additional table file shows this in more detail [see Additional file 1].), likely due to differences in underlying tissue sensitivity. However, this Location factor did not significantly interact with the key outcome measures (Time or Condition), indicating that the exercise-induced hypoalgesia effect was consistent across all measurement sites.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to investigate the acute effects of a low-intensity aerobic warm-up with and without BFR on PPT in healthy individuals and patients with knee pain. Our study demonstrated a significant acute EIH effect across all participants after a 5-minute low-intensity ergometer warm-up (significant main effect of time). Traditional exercise physiology has generally posited that triggering robust EIH requires moderate-to-high mechanical loading to adequately activate high-threshold motor units and descending pain inhibitory pathways [6, 17, 30]. However, our finding was in accordance with emerging evidence suggesting that low-load aerobic exercise can effectively serve as a pain pre-conditioning strategy to initiate the endogenous analgesic network [5, 7]. One possible interpretation is that low-intensity cycling provides a safe analgesic window for patients with knee pain intolerant to high mechanical joint loading, establishing a favorable state for subsequent rehabilitation tasks without exacerbating articular cartilage wear [4, 15, 31].\u003c/p\u003e\n\u003cp\u003eWe found a markedly blunted EIH response in the patients with knee pain. The healthy individuals exhibited an increase in post-condition PPT (+5.55 N), whereas the patients with knee pain showed a severely suppressed increment (+2.13 N). This finding reveals a fundamental abnormality in the central pain processing mechanisms of patients with chronic knee pain. This blunting phenomenon provides compelling experimental evidence for the remodeling of central pain modulation networks in patients with chronic or persistent musculoskeletal pain[10, 11, 32]. Prolonged peripheral nociceptive input leads not only to local tissue hypersensitivity but also triggers central nervous system sensitization, thereby impairing the efficiency of conditioned pain modulation [9, 12, 33]. Whereas healthy individuals can effectively release endogenous opioids and activate the descending inhibitory systems of the rostroventral medulla (RVM) and periaqueductal gray (PAG) under exercise-induced physiological stress, this endogenous mechanism appears dysfunctional in patients with knee pain [14, 34, 35]. Collectively, the remodeling of central pain modulation networks might be the reason for this blunting phenomenon, suggesting that clinical rehabilitation must prioritize the restoration of central pain regulatory mechanisms [36].\u003c/p\u003e\n\u003cp\u003eRegarding the BFR condition, we found that its short-duration application did not confer additional analgesic benefits superior to the standard warm-up. Although extensive literature supports that low-load BFR resistance training can stimulate Group III and IV muscle afferents by accelerating local hypoxia\u0026nbsp;[19-21, 37], the metabolic stress induced by our 5-minute low-intensity aerobic warm-up combined with 70% AOP was likely substantially lower than that generated by traditional BFR protocols [18, 24]. In addition, the mechanical compression and ischemic sensation induced by the BFR tourniquet constitute a heterotopic noxious stimulus. In healthy individuals, this stimulus triggers a pain-inhibits-pain response [13]; however, in patients with knee pain with impaired CPM, this ischemic discomfort translates into a competing nociceptive input, thereby neutralizing potential metabolic analgesic gains [25, 38, 39].\u003c/p\u003e\n\u003cp\u003eMethodologically, our study demonstrated extreme instability and significant elevation in the first recorded value among the four consecutive PPT measurements. This initial measurement error can be attributed to novelty anxiety regarding the algometer probe\u0026apos;s compression, muscle guarding, or hypervigilance toward expected pain [40, 41]. As measurements were repeated, subjects habituated to the mechanical stimulus. Therefore, the mean of the subsequent three trials accurately reflects the stable baseline PPT, suggesting that future clinical pain studies should routinely discard the first PPT measurement to minimize the confounding influence of psychological expectations [42]. Spatial analysis of the three peri-patellar measurement sites revealed a significant main effect of location without interaction with the conditions, indicating natural PPT discrepancies across different anatomical sites\u0026nbsp;[28, 43]. However, the consistent magnitude of analgesia across these distinct regions further supports that EIH is primarily a regional analgesic mechanism mediated by the central nervous system\u0026nbsp;[7, 44].\u003c/p\u003e\n\u003cp\u003eFinally, several limitations of this study should be mentioned. (i) The sample size of the patients with knee pain was relatively small and encompassed a heterogeneous range of pathological states, which precluded sub-group analyses based on specific etiologies. (ii) The cross-sectional design evaluated only the acute effects of a single BFR condition. (iii) Due to the palpable nature of cuff inflation, true blinding to the BFR condition was unfeasible, which might introduce expectation bias, although multiple safeguards were employed during measurements. Future longitudinal randomized controlled trials with larger sample sizes are required to investigate whether chronic BFR aerobic training can induce long-term neuroplastic adaptations in patients with knee pain [8, 21].\u003c/p\u003e\n\u003cp\u003eIn conclusion, our findings revealed that a low-intensity aerobic warm-up contributes to acute analgesia, but this endogenous protective mechanism exhibits significant pathological blunting in patients with knee pain. The transient superimposition of BFR did not yield additional acute analgesic benefits. Rehabilitation interventions for patients with knee pain require the exploration of BFR protocols with higher metabolic loads or longer durations to unlock its full analgesic potential.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study demonstrated that a 5-minute low-intensity cycling warm-up effectively elicited immediate EIH. However, this endogenous analgesic response was significantly blunted in patients with knee pain, reflecting a potential impairment in central pain modulation. Regarding the BFR condition, the concurrent application of short-duration occlusion did not yield additive hypoalgesic benefits. One possible interpretation is that higher metabolic stress or longer occlusion durations might be required to trigger BFR-mediated analgesia. Methodologically, the initial PPT measurement should be excluded in future clinical assessments to mitigate novelty-induced sensitization and ensure data reliability. Collectively, although low-load active warm-ups remain clinically valuable for pain management, future research should optimize BFR protocols to effectively address the blunted EIH response in patients with knee pain.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eEIH\u003c/strong\u003e Exercise-Induced Hypoalgesia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBFR\u003c/strong\u003e Blood Flow Restriction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePPT\u003c/strong\u003e Pressure Pain Threshold\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAOP\u003c/strong\u003e Arterial Occlusion Pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLMM\u003c/strong\u003e Linear Mixed Model\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCPM\u0026nbsp;\u003c/strong\u003eConditioned Pain Modulation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e Body Mass Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNRS\u0026nbsp;\u003c/strong\u003eNumeric Rating Scale\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSD\u003c/strong\u003e Standard Deviation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRVM\u0026nbsp;\u003c/strong\u003eRostroventral Medulla\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePAG\u0026nbsp;\u003c/strong\u003ePeriaqueductal Gray\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Shanghai Pudong Hospital (Approval No.2023-WZ-03). All participants provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eWe confirm that all data and photographs were obtained with the subjects\u0026apos; informed consent. They voluntarily agreed to their use for publication, and the consent records are available for verification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the National Natural Science Foundation of China (82102665) and the Shanghai Sailing Program (21YF1404600).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e \u003cstrong\u003e\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003eHW and QL conceived and designed the study. YFZ, PZ, and FQ performed the experiments and collected the data. BP, HQ, and XX were responsible for data curation and statistical analysis. ZB and YC assisted in the investigation and methodology. YFZ and PZ drafted the original manuscript. LC and YH reviewed and edited the manuscript. HW supervised the entire project. All authors have read and agreed to the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe would like to express our gratitude to all the volunteers who participated in this study. We would like to express our sincere gratitude to Shuqin Liu, Ziyi Zhou, and Xiaoyue Zhai for their efforts in data collation and photo shooting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of AI Usage:\u0026nbsp;\u003c/strong\u003eDuring the preparation of this work, the authors utilized artificial intelligence tools solely for language polishing and grammatical correction to enhance readability. No AI tools were used to generate scientific content or data. The authors have reviewed the final text and take full responsibility for the content of this publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study\u003c/strong\u003e. \u003cem\u003eAnnals of the rheumatic diseases \u003c/em\u003e2014, \u003cstrong\u003e73\u003c/strong\u003e(7):1323-1330.\u003c/li\u003e\n\u003cli\u003ePeat G, McCarney R, Croft P: \u003cstrong\u003eKnee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care\u003c/strong\u003e. \u003cem\u003eAnnals of the rheumatic diseases \u003c/em\u003e2001, \u003cstrong\u003e60\u003c/strong\u003e(2):91-97.\u003c/li\u003e\n\u003cli\u003eBannuru RR, Osani MC, Vaysbrot EE, Arden NK, 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\u003cstrong\u003e46\u003c/strong\u003e(3):168-176.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"555\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHealthy Group\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n = 26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKnee Pain Group\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n = 12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 555px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e29.50\u0026plusmn;8.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e30.75\u0026plusmn;8.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.875\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eGender (Male / Female), n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e15 / 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e8 / 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.728\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eBMI (kg/m\u0026sup2;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e22.08\u0026plusmn;2.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e21.80\u0026plusmn;3.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.801\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eEducation (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e16.00\u0026plusmn;2.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e15.33\u0026plusmn;2.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.843\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eExercise Habits (hours/week)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e1.79\u0026plusmn;2.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e2.04\u0026plusmn;2.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.509\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 555px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCondition Parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eArterial Occlusion Pressure (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e164.73\u0026plusmn;28.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e159.33\u0026plusmn;23.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eBFR Side (Left / Right), n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e13 / 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e6 / 6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 555px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Characteristics\u0026nbsp;\u003c/strong\u003e(Pain Group only)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eSymptom Duration (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e12.75\u0026plusmn;10.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eBaseline Pain Intensity (NRS, 0-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e3.5\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 555px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathology Type\u003c/strong\u003e, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003ePost-operative ACL Reconstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e5 (41.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eMeniscal Injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e3 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 237px;\"\u003e\n \u003cp\u003eKnee Osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e4 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote:\u0026nbsp;Data are presented as mean \u0026plusmn; standard deviation (SD) for continuous variables and frequency (n) for categorical variables. \u003cem\u003ep\u003c/em\u003e-values were calculated using independent t-tests for continuous variables and Chi-square tests for categorical variables. BMI: Body Mass Index; NRS: Numeric Rating Scales; ACL: Anterior Cruciate Ligament.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-sports-science-medicine-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ssmr","sideBox":"Learn more about [BMC Sports Science, Medicine and Rehabilitation](http://bmcsportsscimedrehabil.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ssmr/default.aspx","title":"BMC Sports Science, Medicine and Rehabilitation","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Exercise-induced hypoalgesia, Knee pain, Warm-up, Pressure pain threshold, Blood flow restriction, Endogenous pain modulation","lastPublishedDoi":"10.21203/rs.3.rs-9380597/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9380597/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eExercise-induced hypoalgesia (EIH) is vital for rehabilitation, but its efficacy in patients with knee pain remains controversial. Blood flow restriction (BFR) might augment analgesia through metabolic accumulation. This study aimed to investigate the acute analgesic impact of a low-intensity warm-up with or without BFR and to compare EIH responses between healthy individuals and patients with knee pain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThirty-eight participants (healthy individuals: n\u0026thinsp;=\u0026thinsp;26; patients with knee pain: n\u0026thinsp;=\u0026thinsp;12) were enrolled in a randomized, single-session, within-subject split-body protocol. A 5-minute low-intensity ergometer warm-up was performed. BFR (70% arterial occlusion pressure) was applied to one limb (randomized in healthy, fixed to painful limb in patients), and the contralateral limb was utilized as a simultaneous control. Pressure pain thresholds (PPT) were measured at three peri-patellar sites pre- and post-condition using a Latin Square design. Data were analyzed via Linear Mixed Models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA significant main effect of time was observed (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating that warm-up significantly increased PPT across all conditions. Crucially, a significant Group \u0026times; Time interaction (p\u0026thinsp;=\u0026thinsp;0.001) revealed that the magnitude of exercise-induced hypoalgesia was blunted in the knee pain group (PPT\u0026thinsp;+\u0026thinsp;2.13 N) compared to the healthy group (PPT\u0026thinsp;+\u0026thinsp;5.55 N). No significant Group \u0026times; Condition \u0026times; Time interaction was found (p\u0026thinsp;=\u0026thinsp;0.374), suggesting that BFR provided no superior acute analgesia over standard warm-up. Additionally, the main effect of location was identified (p\u0026thinsp;=\u0026thinsp;0.005), but this did not interact with the condition effect.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eA low-intensity ergometer warm-up effectively induces acute analgesia, but this protective mechanism exhibits significant pathological blunting in patients with knee pain, suggesting that endogenous pain modulation might be impaired. The transient superimposition of BFR did not yield additional acute analgesic benefits. Therefore, rehabilitation interventions for patients with knee pain might require BFR protocols with increased pressure intensities or sustained workloads to unlock potential hypoalgesic benefits.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eChinese Clinical Trial Registry ChiCTR2300069386 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.chictr.org.cn/\u003c/span\u003e\u003cspan address=\"https://www.chictr.org.cn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, registered on 15 March 2023)\u003c/p\u003e","manuscriptTitle":"Blunted Exercise-Induced Hypoalgesia After a 5-Min Low-Intensity Ergometer Exercise in Knee Pain vs Healthy Controls: A Randomized Within-Subject Comparison of BFR vs Non- BFR Warm-Up","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-06 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