Association of Muscle Quality and Pain in Adults With Symptomatic Knee Osteoarthritis, Independent of Muscle Strength: Findings From a Cross-Sectional Study.

OBJECTIVE: Knee osteoarthritis (OA) is a leading cause of chronic pain in adults and shows wide interindividual variability, with peripheral and central factors contributing to the pain experience. Periarticular factors, such as muscle quality (eg, echo intensity [EI] and shear wave velocity [SWV]), may contribute to knee OA pain; however, the role of muscle quality in OA symptoms has yet to be fully established. METHODS: Twenty-six adults (age >50 years) meeting clinical criteria for knee OA were included in this cross-sectional study. Quantitative ultrasound imaging was used to quantify EI and SWV in the rectus femoris of the index leg. Pearson correlations followed by multiple linear regression was used to determine associations between muscle quality and pain, controlling for strength, age, sex, and body mass index. RESULTS: EI and SWV were significantly associated with movement-evoked pain (b = 0.452-0.839, P = 0.024-0.029). Clinical pain intensity was significantly associated with SWV (b = 0.45, P = 0.034), as were pressure pain thresholds at the medial (b = -0.41, P = 0.025) and lateral (b = -0.54, P = 0.009) index knee joint line, adjusting for all covariates. Pain interference was significantly associated with knee extension strength (b = -0.51, P = 0.041). CONCLUSION: These preliminary findings suggest that EI and SWV may impact knee OA pain and could serve as malleable treatment targets. Findings also demonstrate that muscle quality is a unique construct, distinct from muscle strength, which may impact pain and treatment outcomes. More research is needed to fully understand the role of muscle quality in knee OA.

Massage Therapy as a Self-Management Strategy for Musculoskeletal Pain and Chronic Conditions: A Systematic Review of Feasibility and Scope.

Background: Musculoskeletal pain and chronic conditions are associated with deteriorating pain, stress, anxiety, and health-related quality of life (HR-QOL). There is emerging evidence that performing massage therapy as self-management (MTSM) is a viable approach to alleviate these symptoms across various clinical populations. However, a significant gap remains on the effectiveness and limitation of MTSM usage as no systematic review has been conducted to comprehensively evaluate and synthesize the scope, feasibility, and efficacy of MTSM. This systematic review aimed to investigate the effect of MTSM on common symptoms of musculoskeletal and chronic conditions, followed by identifying characteristics of MTSM dosage, setting, and adherence for formulating themes. Methods: A systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method, which involved searching seven electronic databases, including Medline (OVID), CINAHL (EBSCO), PEDro, Web of Science (Clarivate), PsycINFO (EBSCO), Google Scholar, and EMBASE (Elsevier) from inception to January 2023. Clinical studies were eligible if they included MTSM, and massage treatment was more than 50% of the intervention. The quality of studies was assessed using the Effective Public Health Practice Project Quality Assessment Tool. Target variables were extracted, including study design, participants' characteristics, outcome measures, massage dosage (duration, frequency, and timing), training setting, provider of massage training, adherence to the MTSM intervention, comparator, and key findings. Results: A total of 17 studies were evaluated and included 770 participants (female: N = 606) with musculoskeletal pain or chronic conditions. The emerged themes for MTSM utilization consisted of arthritis pain (knee, n = 3; neck, n = 1, hand, n = 2), neck and back pain (n = 4), and stress and anxiety (n = 3). Prescribed self-administered massage duration ranged from a single session to a maximum of 8-12 weeks, where 4 weeks (n = 8) was the most commonly prescribed duration. Out of 11 studies that used MTSM as a solo modality, 7 studies (41.2%) showed significant improvement in the outcome measures such as chronic neck and back pain, stress or anxiety, fatigue, quality of sleep, and HR-QOL. In addition, health benefits, including anxiety, depression, pain intensity, and pain threshold, were observed in six studies (35.3%) where MTSM was applied as a coadjuvant modality, which was combined with therapist-applied massage and physiotherapy. Conclusions: These findings support that MTSM is a viable approach to enhance the benefit of therapist-applied massage or as a solo modality for symptom management of musculoskeletal pain and chronic conditions. The review provides suggestions for design improvement, such as reporting participants' adherence to the prescribed massage regimen, that would be informative for providing a robust understanding of the magnitude or the extent to which MTSM is effective. Future studies on MTSM intervention are encouraged to use a theoretical framework and validated measures for determining and facilitating treatment fidelity.

Accelerated Brain Aging Mediates the Association Between Psychological Profiles and Clinical Pain in Knee Osteoarthritis.

Chronic pain is driven by factors across the biopsychosocial spectrum. Previously, we demonstrated that magnetic resonance images (MRI)-based brain-predicted age differences (brain-PAD: brain-predicted age minus chronological age) were significantly associated with pain severity in individuals with chronic knee pain. We also previously identified four distinct, replicable, multidimensional psychological profiles significantly associated with clinical pain. The brain aging-psychological characteristics interface in persons with chronic pain promises elucidating factors contributing to their poor health outcomes, yet this relationship is barely understood. That is why we examined the interplay between the psychological profiles in participants having chronic knee pain impacting function, brain-PAD, and clinical pain severity. Controlling for demographics and MRI scanner, we compared the brain-PAD among psychological profiles at baseline (n = 164) and over two years (n = 90). We also explored whether profile-related differences in pain severity were mediated by brain-PAD. Brain-PAD differed significantly between profiles (ANOVA's omnibus test, P = .039). Specifically, participants in the profile 3 group (high negative/low positive emotions) had an average brain-PAD ∼4 years higher than those in profile- (low somatic reactivity), with P = .047, Bonferroni-corrected, and than those in profile 2 (high coping), with P = .027, uncorrected. Repeated measures ANOVA revealed no significant change in profile-related brain-PAD differences over time, but there was a significant decrease in brain-PAD for profile 4 (high optimism/high positive affect), with P = .045. Moreover, profile-related differences in pain severity at baseline were partly explained by brain-PAD differences between profile 3 and 1, or 2; but brain-PAD did not significantly mediate the influence of variations in profiles on changes in pain severity over time. PERSPECTIVE: Accelerated brain aging could underlie the psychological-pain relationship, and psychological characteristics may predispose individuals with chronic knee pain to worse health outcomes via neuropsychological processes.

Weight-cycling over 6 years is associated with pain, physical function and depression in the Osteoarthritis Initiative cohort.

Body weight significantly impacts health and quality of life, and is a leading risk factor for the development of knee osteoarthritis (OA). Weight cycling may have more negative health consequences compared to steady high or low weight. Using the Osteoarthritis Initiative dataset, we investigated the effects of weight cycling on physical function, quality of life, and depression over 72-months compared to stable or unidirectional body weight trajectories. Participants (n = 731) had knee OA and were classified as: (1) stable-low (BMI < 25), (2) stable-overweight (BMI = 25-29.9), and (3) stable-obese (BMI ≥ 30); (4) steady-weight-loss; (5) steady-weight-gain (weight loss/gain ≥ 2.2 kg every 2-years); (6) gain-loss-gain weight cycling, and (7) loss-gain-loss weight cycling (weight loss/gain with return to baseline), based on bi-annual assessments. We compared Knee Injury and Osteoarthritis Outcome Knee-Related Quality of Life, Function in Sports and Recreation, Physical Activity in the Elderly, Short Form SF-12, repeated chair rise, 20-m gait speed, and Center for Epidemiological Studies Depression using repeated-measures ANOVA. The steady weight loss group demonstrated the worst pain, physical function, and depressive symptoms over time (p's < 0.05). More research is needed to confirm these findings, and elucidate the mechanisms by which steady weight loss is associated with functional decline in knee OA.

Brain-predicted age difference mediates the association between PROMIS sleep impairment, and self-reported pain measure in persons with knee pain.

Knee pain, the most common cause of musculoskeletal pain (MSK), constitutes a severe public health burden. Its neurobiological causes, however, remain poorly understood. Among many possible causes, it has been proposed that sleep problems could lead to an increase in chronic pain symptomatology, which may be driven by central nervous system changes. In fact, we previously found that brain cortical thickness mediated the relationship between sleep qualities and pain severity in older adults with MSK. We also demonstrated a significant difference in a machine-learning-derived brain-aging biomarker between participants with low-and high-impact knee pain. Considering this, we examined whether brain aging was associated with self-reported sleep and pain measures, and whether brain aging mediated the relationship between sleep problems and knee pain. Exploratory Spearman and Pearson partial correlations, controlling for age, sex, race and study site, showed a significant association of brain aging with sleep related impairment and self-reported pain measures. Moreover, mediation analysis showed that brain aging significantly mediated the effect of sleep related impairment on clinical pain and physical symptoms. Our findings extend our prior work demonstrating advanced brain aging among individuals with chronic pain and the mediating role of brain-aging on the association between sleep and pain severity. Future longitudinal studies are needed to further understand whether the brain can be a therapeutic target to reverse the possible effect of sleep problems on chronic pain.

Brain-predicted age difference estimated using DeepBrainNet is significantly associated with pain and function-a multi-institutional and multiscanner study.

ABSTRACT: Brain age predicted differences (brain-PAD: predicted brain age minus chronological age) have been reported to be significantly larger for individuals with chronic pain compared with those without. However, a debate remains after one article showed no significant differences. Using Gaussian Process Regression, an article provides evidence that these negative results might owe to the use of mixed samples by reporting a differential effect of chronic pain on brain-PAD across pain types. However, some remaining methodological issues regarding training sample size and sex-specific effects should be tackled before settling this controversy. Here, we explored differences in brain-PAD between musculoskeletal pain types and controls using a novel convolutional neural network for predicting brain-PADs, ie, DeepBrainNet. Based on a very large, multi-institutional, and heterogeneous training sample and requiring less magnetic resonance imaging preprocessing than other methods for brain age prediction, DeepBrainNet offers robust and reproducible brain-PADs, possibly highly sensitive to neuropathology. Controlling for scanner-related variability, we used a large sample (n = 660) with different scanners, ages (19-83 years), and musculoskeletal pain types (chronic low back [CBP] and osteoarthritis [OA] pain). Irrespective of sex, brain-PAD of OA pain participants was ∼3 to 4.7 years higher than that of CBP and controls, whereas brain-PAD did not significantly differ among controls and CBP. Moreover, brain-PAD was significantly related to multiple variables underlying the multidimensional pain experience. This comprehensive work adds evidence of pain type-specific effects of chronic pain on brain age. This could help in the clarification of the debate around possible relationships between brain aging mechanisms and pain.

Pain interference mediates the association between epigenetic aging and grip strength in middle to older aged males and females with chronic pain.

Introduction: Chronic pain is one of the leading causes of disability that may accelerate biological aging and reduce physical function. Epigenetic clocks provide an estimate of how the system ages and can predict health outcomes such as physical function. Physical function declines may be attributed to decreases in muscle quality due to disuse that can be measured quickly and noninvasively using grip strength. The purpose of this study was to explore the associations among self-reported pain, grip strength, and epigenetic aging in those with chronic pain. Methods: Participants (57.91 ± 8.04 years) completed pain questionnaires, a blood draw and hand grip strength task. We used an epigenetic clock previously associated with knee pain (DNAmGrimAge), and used the subsequent difference of predicted epigenetic age from chronological age (DNAmGrimAge-Difference). Results: Exploratory pathway analyses revealed that pain intensity mediated the association between DNAmGrimAge-difference and handgrip strength in males only (ß = -0.1115; CI [-0.2929, -0.0008]) and pain interference mediated the association between DNAmGrimAge-difference and handgrip strength in males ß = -0.1401; CI [-0.3400, -0.0222]), and females (ß = -0.024; CI [-0.2918, -0.0020]). Discussion: Chronic knee pain may accelerate epigenetic aging processes that may influence handgrip strength in older age adults. Chronic pain could be a symptom of the aging body thus contributing to declines in musculoskeletal function in later life.

Brain predicted age difference mediates pain impact on physical performance in community dwelling middle to older aged adults.

The purpose of the study was to examine associations between physical performance and brain aging in individuals with knee pain and whether the association between pain and physical performance is mediated by brain aging. Participants (n=202) with low impact knee pain (n=111), high impact knee pain (n=60) and pain-free controls (n=31) completed self-reported pain, magnetic resonance imaging (MRI), and a Short Physical Performance Battery (SPPB) that included balance, walking, and sit to stand tasks. Brain predicted age difference, calculated using machine learning from MRI images, significantly mediated the relationships between walking and knee pain impact (CI: -0.124; -0.013), walking and pain-severity (CI: -0.008; -0.001), total SPPB score and knee pain impact (CI: -0.232; -0.025), and total SPPB scores and pain-severity (CI: -0.019; -0.001). Brain-aging begins to explain the association between pain and physical performance, especially walking. This study supports the idea that a brain aging prediction can be calculated from shorter duration MRI sequences and possibly implemented in a clinical setting to be used to identify individuals with pain who are at risk for accelerated brain atrophy and increased likelihood of disability.

Cross-Sectional Brain-Predicted Age Differences in Community-Dwelling Middle-Aged and Older Adults with High Impact Knee Pain.

Purpose: Knee OA-related pain varies in impact across individuals and may relate to central nervous system alterations like accelerated brain aging processes. We previously reported that older adults with chronic musculoskeletal pain had a significantly greater brain-predicted age, compared to pain-free controls, indicating an "older" appearing brain. Yet this association is not well understood. This cross-sectional study examines brain-predicted age differences associated with chronic knee osteoarthritis pain, in a larger, more demographically diverse sample with consideration for pain's impact. Patients and Methods: Participants (mean age = 57.8 ± 8.0 years) with/without knee OA-related pain were classified according to pain's impact on daily function (ie, impact): low-impact (n=111), and high-impact (n=60) pain, and pain-free controls (n=31). Participants completed demographic, pain, and psychosocial assessments, and T1-weighted magnetic resonance imaging. Brain-predicted age difference (brain-PAD) was compared across groups using analysis of covariance. Partial correlations examined associations of brain-PAD with pain and psychosocial variables. Results: Individuals with high-impact chronic knee pain had significantly "older" brains for their age compared to individuals with low-impact knee pain (p < 0.05). Brain-PAD was also significantly associated with clinical pain, negative affect, passive coping, and pain catastrophizing (p's<0.05). Conclusion: Our findings suggest that high impact chronic knee pain is associated with an older appearing brain on MRI. Future studies are needed to determine the impact of pain-related interference and pain management on somatosensory processing and brain aging biomarkers for high-risk populations and effective intervention strategies.

Clinical vitamin D levels are associated with insular volume and inferior temporal gyrus white matter surface area in community-dwelling individuals with knee pain.

Context: Vitamin D is an essential, fat soluble micronutrient long-known for its effects on calcium homeostasis and bone health. With advances in technology, it is being discovered that Vitamin D exerts its effects beyond the musculoskeletal system. Vitamin D has since been noted in nervous system health and functioning, and is becoming a target of interest in brain health, aging, and chronic pain outcomes. Objectives: We and others have previously shown that deficient Vitamin D status is associated with greater pain severity across a variety of conditions, however the reason as to why this relationship exists is still being understood. Here, we sought to examine associations between Vitamin D status and brain structure in those with chronic knee pain. Methods: Structural MRI imaging techniques and whole brain analyses were employed and serum Vitamin D were collected on 140 participants with chronic pain. Covariates included age, sex, race and site, as these data were collected at two separate institutions. ANOVAs using the clinical cut points for Vitamin D status (deficient, insufficient, and optimal) as well as continuous regression-based Vitamin D effects were employed to observe differences in brain volume. P-value was set to 0.017 after correction for multiple comparisons. Results: We discovered that individuals in our sample (age = 50+; 63.6% female; 52.1% Non-Hispanic Black) who were either clinically deficient (<20 ng/mL) or insufficient (20-30 ng/mL) in serum Vitamin D had significant differences in the gray matter of the left circular insular cortex, left inferior temporal gyrus, right middle temporal gyrus, as well as decreased white matter surface area in the right inferior temporal gyrus compared to those considered to have optimal levels (>30 ng/mL) of serum Vitamin D. Conclusion: Evidence from these data suggests that Vitamin D, or lack thereof, may be associated with pain outcomes by mediating changes in regions of the brain known to process and interpret pain. More research understanding this phenomenon as well as the effects of Vitamin D supplementation is warranted.

Epigenetic age predictors in community-dwelling adults with high impact knee pain.

Gerontological research reveals considerable interindividual variability in aging phenotypes, and emerging evidence suggests that high impact chronic pain may be associated with various accelerated biological aging processes. In particular, epigenetic aging is a robust predictor of health-span and disability compared to chronological age alone. The current study aimed to determine whether several epigenetic aging biomarkers were associated with high impact chronic pain in middle to older age adults (44-78 years old). Participants (n = 213) underwent a blood draw, demographic, psychosocial, pain and functional assessments. We estimated five epigenetic clocks and calculated the difference between epigenetic age and chronological age, which has been previously reported to predict overall mortality risk, as well as included additional derived variables of epigenetic age previously associated with pain. There were significant differences across Pain Impact groups in three out of the five epigenetic clocks examined (DNAmAge, DNAmPhenoAge and DNAmGrimAge), indicating that pain-related disability during the past 6 months was associated with markers of epigenetic aging. Only DNAmPhenoAge and DNAmGrimAge were associated with higher knee pain intensity during the past 48 h. Finally, pain catastrophizing, depressive symptomatology and more neuropathic pain symptoms were significantly associated with an older epigenome in only one of the five epigenetic clocks (i.e. DNAmGrimAge) after correcting for multiple comparisons (corrected p's < 0.05). Given the scant literature in relation to epigenetic aging and the complex experience of pain, additional research is needed to understand whether epigenetic aging may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.

Persistent Non-pharmacological Pain Management and Brain-Predicted Age Differences in Middle-Aged and Older Adults With Chronic Knee Pain.

Chronic pain has been associated with changes in pain-related brain structure and function, including advanced brain aging. Non-pharmacological pain management is central to effective pain management. However, it is currently unknown how use of non-pharmacological pain management is associated with pain-related brain changes. The objective of the current study was to examine the association between brain-predicted age difference and use of non-pharmacological pain management (NPM) in a sample of middle-aged and older adults with and without chronic knee pain across two time points. One-hundred and 12 adults (mean age = 57.9 ± 8.2 years) completed sociodemographic measures, clinical pain measures, structural T1-weighted brain magnetic resonance imaging, and self-reported non-pharmacological pain management. Using a validated approach, we estimated a brain-predicted age difference (brain-PAD) biomarker, calculated as brain-predicted age minus chronological age, and the change in brain-PAD across 2 years. Repeated measures analysis of covariance was conducted to determine associations of non-pharmacological pain management and brain-PAD, adjusting for age, sex, study site, and clinical pain. There was a significant time*pain/NPM interaction effect in brain-PAD (p < 0.05). Tests of simple main effects indicated that those persistently using NPM had a "younger" brain-PAD over time, suggesting a potential protective factor in persistent NPM use. Future studies are warranted to determine the influence of NPM in brain aging and pain-related neurological changes.

Experimental Pain Phenotype Profiles in Community-dwelling Older Adults.

OBJECTIVES: Pain sensitivity and the brain structure are critical in modulating pain and may contribute to the maintenance of pain in older adults. However, a paucity of evidence exists investigating the link between pain sensitivity and brain morphometry in older adults. The purpose of the study was to identify pain sensitivity profiles in healthy, community-dwelling older adults using a multimodal quantitative sensory testing protocol and to differentiate profiles based on brain morphometry. MATERIALS AND METHODS: This study was a secondary analysis of the Neuromodulatory Examination of Pain and Mobility Across the Lifespan (NEPAL) study. Participants completed demographic and psychological questionnaires, quantitative sensory testing, and a neuroimaging session. A Principal Component Analysis with Varimax rotation followed by hierarchical cluster analysis identified 4 pain sensitivity clusters (the "pain clusters"). RESULTS: Sixty-two older adults ranging from 60 to 94 years old without a specific pain condition (mean [SD] age=71.44 [6.69] y, 66.1% female) were analyzed. Four pain clusters were identified characterized by (1) thermal pain insensitivity; (2) high pinprick pain ratings and pressure pain insensitivity; (3) high thermal pain ratings and high temporal summation; and (4) thermal pain sensitivity, low thermal pain ratings, and low mechanical temporal summation. Sex differences were observed between pain clusters. Pain clusters 2 and 4 were distinguished by differences in the brain cortical volume in the parieto-occipital region. DISCUSSION: While sufficient evidence exists demonstrating pain sensitivity profiles in younger individuals and in those with chronic pain conditions, the finding that subgroups of experimental pain sensitivity also exist in healthy older adults is novel. Identifying these factors in older adults may help differentiate the underlying mechanisms contributing to pain and aging.

Epigenetic aging, knee pain and physical performance in community-dwelling middle-to-older age adults.

Knee pain is a leading cause of disability in the aging population and may indirectly accelerate biological aging processes. Chronological aging increases the risk of developing of knee pain and knee pain reduces physical function; however, limited data exist on how epigenetic aging, a known hallmark of biological aging shown to predict health span and mortality, may influence this relationship. The purpose of this study was to examine whether decreased physical performance associated with knee pain is mediated by markers of epigenetic aging. Participants (57.91 ± 8.04 years) with low impact knee pain (n = 95), high impact knee pain (n = 53) and pain-free controls (n = 26) completed self-reported pain, a blood draw and a short physical performance battery (SPPB) that included balance, walking, and sit to stand tasks. We employed an epigenetic clock previously associated with knee pain and shown to predict overall mortality risk (DNAmGrimAge). Bootstrapped-mediation analyses were used to determine associations of DNAmGrimAge and SPPB between pain groups. Those with high impact and low impact pain had a biologically older epigenetic age (5.14y ± 5.66 and 1.32y ± 5.41, respectively). However, while there were direct effects of pain on overall physical performance, these were not explained by epigenetic aging. Epigenetic aging only mediated the effect of pain on balance performance. Future work is needed to examine pain's impact on biological aging processes including epigenetic aging and its ultimate effect on physical function measures known to predict health span and mortality.

Applying the NIA Health Disparities Research Framework to Identify Needs and Opportunities in Chronic Musculoskeletal Pain Research.

Disparities in the experience of chronic musculoskeletal pain in the United States stem from a confluence of a broad array of factors. Organized within the National Institute on Aging Health Disparity Research Framework, a literature review was completed to evaluate what is known and what is needed to move chronic musculoskeletal pain research forward specific to disproportionately affected populations. Peer-reviewed studies published in English, on human adults, from 2000 to 2019, and conducted in the United States were extracted from PubMed and Web of Science. Articles were reviewed for key words that focused on underrepresented ethnic/race groups with chronic musculoskeletal pain applying health factor terms identified in the NIAHealth Disparity Research Framework four levels of analysis: 1) environmental, 2) sociocultural, 3) behavioral, and 4) biological. A total of 52 articles met inclusion criteria. There were limited publications specific to underrepresented ethnic/race groups with chronic musculoskeletal pain across all levels with particular research gaps under sociocultural and biological categories. Current limitations in evidence may be supplemented by a foundation of findings specific to the broader topic of "chronic pain" which provides guidance for future investigations. Study designs including a focus on protective factors and multiple levels of analyses would be particularly meritorious. PERSPECTIVE: Chronic musculoskeletal pain unequally burdens underrepresented ethnic/race groups. In order to move research forward and to systematically investigate the complex array of factors contributing toward health disparities, an organized approach is necessary. Applying the NIA Health Disparities Research Framework, an overview of the current state of evidence specific to chronic musculoskeletal pain and underrepresented ethnic/race groups is provided with future directions identified.

Vulnerable Dispositional Traits and Chronic Pain: Predisposing but not Predetermining.

Dispositional traits can be protective or contribute to increased vulnerability in individuals with chronic pain. This study aims to evaluate the association between two dispositional trait measures, affect balance style and multi-domain trait groups, with psychosocial measures, clinical pain, functional pain, and experimental pain at two years in individuals with chronic knee pain. The study is a prospective analysis of 168 community dwelling individuals aged 45 to 85 years old with knee pain with or at risk for knee osteoarthritis. At baseline, affect balance style and multi-domain trait groups were associated with psychosocial measures, clinical pain, and functional status. At the two-year time point, the multi-domain trait groups were associated with the clinical pain measures. Interestingly, individuals with previously demonstrated vulnerable traits showed more variability in dispositional trait status at the two-year time point compared to those with dispositional traits previously demonstrated as more protective. Findings reiterate that dispositional traits are predisposing but are not predetermining regarding pain-related experiences. PERSPECTIVE: Vulnerable and protective dispositional traits are positively and negatively associated with clinical pain and functional limitations respectively. Although considered relatively stable, a 30-50% shift in dispositional traits was indicated over a two-year period. Findings highlight that dispositional trait are modifiable and thus, predisposing but not predetermining for persisting chronic pain.