Objective Low back pain (LBP) is common, yet many individuals maintain normal activities of daily living despite chronic symptoms and structural changes evident on imaging. We hypothesized that functional resilience, defined as preserved functional capacity despite pain and age‑typical degenerative changes, represents a meaningful clinical phenotype, and that function‑centered outcome measures would better discriminate disability status than structural imaging features.
Methods This study analyzed 347 participants reporting LBP from the Wakayama Spine Study (N=866). Maintained function was defined a priori as Oswestry Disability Index (ODI) ≤20%. We compared those with maintained function (n=220, 63.4%) to those with impairment (n=127) across demographics, lifestyle, metabolic components, physical performance (grip strength, gait speed), and lumbar magnetic resonance imaging (MRI) findings. Multivariable logistic regression among participants with LBP, including age, sex, obesity, metabolic factors, pain intensity, physical performance, and MRI phenotypes, was used to identify independent predictors of functional resilience.
Results Functional resilience was common: 63.0% of LBP participants had ODI ≤20%. Resilient individuals were younger (65.0±11.9 years vs. 74.6±10.9 years, p<0.001) with superior physical performance. In multivariable models, male sex predicted maintained function (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.03–3.00; p<0.05), while obesity (body mass index ≥25 kg/m2) was associated with reduced odds of resilience (OR, 0.50; 95% CI, 0.30–0.84; p<0.01). Standard MRI features, including disc degeneration, Modic changes, and Schmorl nodes, were not independently associated with functional status after adjustment, despite disc degeneration being highly prevalent even among resilient participants (95.4%).
Conclusion These data confirm that functional resilience is common in LBP and is not negated by the presence of structural MRI abnormalities. Among LBP patients, male sex and absence of obesity are independent predictors of maintained function, whereas standard MRI features do not independently predict functional status after age adjustment. Function-centered metrics (ODI, gait speed, grip strength) better discriminate functional status than structural imaging findings.
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The intervertebral disc (IVD) is defined by a uniquely avascular niche characterized by constitutive hypoxia, limited nutrient diffusion, acidic pH, hyperosmolarity, and repetitive mechanical loading. These stressors interact with each other rather than acting in isolation. Reduced endplate transport exacerbates hypoxia and glucose deprivation, driving glycolytic lactate accumulation and acidification. In parallel, acid-osmotic stress perturbs ion homeostasis and mitochondrial membrane potential, while mechanical loading promotes microdamage and inflammatory mediator release. Together they converge on common reactive oxygen species (ROS)-generating nodes, including mitochondrial electron transport disruption, membrane oxidase activation, and endoplasmic reticulum stress, while redox-sensitive signaling by nuclear factor erythroid 2-related factor 2, hypoxia-inducible factor 1/2, nuclear factor kappa B, and mitogen-activated protein kinases integrates metabolic rewiring with catabolic and inflammatory programs. In a healthy state, controlled ROS levels participate in healthy cell signaling and are counterbalanced by antioxidant systems; however, when compensatory capacity is exceeded, oxidative stress becomes self-reinforcing through inflammation-ROS feedback, mitochondrial dysfunction, and impaired proteostasis. This shift drives apoptosis and senescence of disc cells, extracellular breakdown, and endplate, thereby promoting IVD degeneration and creating a microenvironment for vascular and nerve ingrowth associated with discogenic low back pain. We propose an “Adapt-Mitigate-Target” framework that maps (1) physiological adaptation, (2) transition to redox breakdown, and (3) therapeutic opportunities to reduce the oxidative stress burden. We also highlight translational constraints imposed by disc transport barriers and discuss stage-appropriate systemic, local/intradiscal, and mitochondria-directed strategies, alongside a roadmap for biomarkers, precision phenotyping, and combination therapies.
Coccydynia is a painful condition of the coccyx that is frequently misdiagnosed and managed inconsistently. This review summarizes and grades the current evidence on diagnostic strategies and treatment options. We systematically searched the literature and included 42 studies covering conservative, interventional, and surgical management. Based on these data, we propose a current best framework for diagnostic evaluation and therapeutic management. Initial assessment should include detailed history and focused examination with palpation for localized coccygeal tenderness and symptom provocation. Standard anteroposterior and lateral radiographs are recommended mainly to exclude serious pathology, while dynamic sitting-standing radiographs can be considered when mechanical pain is suspected and symptoms persist. Cross-sectional imaging with magnetic resonance imaging or computed tomography (CT) should be reserved for trauma, red-flag features, suspected neoplasm or infection, or inconclusive basic imaging. First-line treatment should consist of education, ergonomic advice, offloading strategies, nonsteroidal anti-inflammatory drugs or other simple analgesics, and physiotherapy, with extracorporeal shock wave therapy having the strongest support. In patients with persistent pain, image-guided diagnostic and therapeutic injections and radiofrequency procedures can provide substantial relief and help select candidates for more invasive treatment. Coccygectomy should be reserved for patients with chronic, function-limiting pain who have failed conservative and interventional care and show concordant findings on assessment, imaging, and diagnostic blocks, while modified incision strategies and minimally invasive techniques may be considered in selected cases.
Low back pain is a leading cause of disability worldwide, with intervertebral disc herniation contributing substantially to its burden. Most patients improve with conservative care, often associated with disc resorption. Although increasingly recognized as a major determinant of recovery, the mechanisms underlying resorption remain poorly understood. Herniated disc tissue induces immune cell infiltration and release of cytokines and proteolytic enzymes, yet standard anti-inflammatory treatments may paradoxically impede this process. Outcomes are also influenced by physical therapy, lifestyle, herniation characteristics, and immunological background, but predictive biomarkers are lacking. This review summarizes the current knowledge gap and explores strategies to harness intrinsic healing for personalized management.
This study aimed to elucidate the efficacy and safety of mesenchymal stromal cell (MSC) therapy for chronic discogenic low back pain (LBP). A systematic literature search was conducted on PubMed/Medline, Scopus, Cochrane, and ClinicalTrials.gov following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines. Eligible studies included published and ongoing clinical trials assessing intradiscal MSC injections in patients with chronic discogenic LBP unresponsive to conservative treatment. Risk-of-bias (RoB) assessment was performed through MINORS (Methodological Index for Non-randomized Studies) and RoB 2 tools. Within- and between-group differences were expressed as means and 95% confidence intervals. Effect sizes were calculated through Cohen d and g. Data from 10 published clinical studies (n=736; 470 in treatment and 266 in control groups) revealed a mean age of 41.5 years and an average follow-up of 21.6 (range, 6–72) months. Various MSC sources were employed, including autologous and allogeneic bone marrow-derived MSCs and adipose-derived MSCs, with doses ranging from 6×10⁶ to over 50×10⁶ cells/disc. Visual analogue scale, Oswestry Disability Index, and quality-of-life questionnaires indicated modest improvements in pain, disability, and functional status. Additionally, magnetic resonance imaging assessments occasionally demonstrated increased disc hydration and stabilization or improvement of Pfirrmann grade. Data from 8 ongoing trials (n=498 participants; 276 treatment, 222 control) with follow-up periods ranging 6–24 months further corroborate the feasibility and safety of MSC-based interventions. MSC therapy is a biologically-driven approach for managing chronic discogenic LBP. While preliminary data support its potential to alleviate pain and improve disc integrity, further high-quality, standardized trials are necessary to optimize treatment protocols and confirm long-term clinical benefits.
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Objective To explore and validate clinical magnetic resonance spectroscopy (MRS) biomarkers associated with patient-reported symptoms in intervertebral disc degeneration, and to further elucidate the pathogenic mechanisms linking these symptoms to MRS biomarkers via an integrative multiomics approach.
Methods Patients categorized into the predominant lipids peak (pLP) group and the non-pLP group based on MRS spectrum lipids peak. Nucleus pulposus cells underwent lipidomics, proteomics and functional experiments. Outcome measures compared, and Pearson correlation coefficient evaluated relationships between symptoms, interleukin (IL)-17 immune-positive cells, and lipid contents. Multivariate linear analysis was employed to analyze the contributions of various variables to patient-reported symptoms.
Results The pLP group exhibited significantly higher preoperative visual analogue scale (VAS)-back scores (6.5 vs. 4.7, p<0.01) and Oswestry Disability Index (ODI) scores (63.3% vs. 51.2%, p<0.01) compared to the non-pLP group. The multiomics analysis revealed the pLP group was characterized by lipid droplets accumulation in nucleus pulposus cells, and the activation of interleukin-17 (IL-17) inflammatory pathway. Preoperative VAS-back and ODI scores showed positive correlations with the expressions of IL-17 (r=0.555, p<0.001; r=0.566, p<0.001) and the relative lipid contents (r=0.567, p<0.001; r=0.561, p<0.001). Multivariate linear analysis revealed that percentage of IL-17 positive cells and the relative triglyceride contents were associated with preoperative VAS-back pain (p=0.021, p=0.046).
Conclusion Patients with the MRS pLP spectrum showed reduced quality of life and upregulation of the lipid droplets-IL-17 inflammatory pathway in nucleus pulposus cells. Inflammatory factors contribute significantly to chronic low back pain development and progression, affecting patient-reported symptoms. The MRS lipids peak may serve as a potential biomarker for diagnosing and monitoring low back pain.
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Neuropathic pain remains a significant clinical challenge due to the limited efficacy and sustainability of existing pharmacological treatments, underscoring the urgent need for mechanism-based therapeutic strategies. In recent years, gene-targeted interventions have emerged as promising modalities capable of modulating key molecular pathways implicated in chronic pain. Approaches such as antisense oligonucleotides and RNA interference have demonstrated encouraging preclinical results by selectively downregulating pain-associated genes. Based on these developments, genome-editing technologies—particularly the clustered regularly interspaced short palindromic repeats (CRISPR) system—have enabled more precise and long-lasting modifications at both the DNA and RNA levels. This review highlights how CRISPR-based approaches in addressing the critical issues of specificity and long-term efficacy in pain gene therapy and exploring the functional roles of key gene targets and regulatory elements. Although challenges such as off-target activity and immunogenic responses remain, growing preclinical evidence supports the feasibility of CRISPR-based approaches in neuropathic pain. Collectively, these developments position CRISPR as a transformative tool to innovate the standard care for persistent pain syndromes and contribute to broader biomedical and pharmaceutical developments through continued refinement of targeting strategies and safety profiles.
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Postoperative pain is an inevitable consequence of spine surgery, yet there remains no universal consensus on the optimal pain management strategy. The complexity of spine procedures, coupled with patient variability, necessitates a multifaceted approach to pain control. Over time, numerous strategies have emerged, each with varying levels of effectiveness. Pharmacological approaches, including multimodal analgesia, local anesthetic infusions, and gabapentinoids, provide relief for both acute and chronic pain. Additionally, perioperative strategies such as enhanced recovery after surgery (ERAS) protocols have demonstrated benefits in optimizing pain control and recovery outcomes. Beyond pharmacological interventions, physical therapy has become a cornerstone of postoperative pain management, aiding in functional recovery and reducing reliance on medications. For patients with refractory or chronic pain, neuromodulatory techniques such as spinal cord stimulation and intrathecal injections offer alternative solutions. Despite the breadth of evidence-based strategies available, limitations persist, including opioid dependence, the complexity of multimodal regimens leading to suboptimal compliance, and cases of refractory pain. These challenges underscore the importance of tailoring pain management approaches to individual patient needs, ensuring a balance between effectiveness and safety. This narrative review of evidence seeks to explore the multifaceted nature of pain management following spine surgery, highlighting the challenges and evolving strategies in optimizing patient outcomes.
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Objective Preoperative opioid misuse is associated with worse postoperative outcomes. This prospective longitudinal cohort study evaluated the association between preoperative opioid misuse and prolonged pain and opioid use after elective spine surgery; and examined postoperative trajectories of patient-reported outcomes over one year.
Methods Fifty-two patients undergoing elective spine surgery completed presurgical and weekly postoperative longitudinal assessments of pain and opioid use and monthly assessments of depression, anxiety, sleep disturbance, and physical function. Cox regression analyzed the effect of preoperative opioid misuse on time to pain and opioid cessation while linear mixed-effects models examined longitudinal changes in postoperative outcomes.
Results Adjusting for age, sex, operative region, number of spinal levels, and any preoperative opioid use, preoperative opioid misuse (COMM-Positive) was associated with a delayed return to baseline opioid dose (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.14–0.88; p=0.02) and delayed opioid cessation (HR, 0.25; 95% CI, 0.09–0.59; p=0.008). All patients experienced comparable reductions in current and average pain intensity, and pain interference over time. COMM-Positive patients reported a normalization of postoperative anxiety and depression 1 month after surgery with a rebound at 3 months while patients without preoperative opioid misuse remained stable over time.
Conclusion Preoperative opioid misuse is a significant risk factor for delayed opioid cessation even after adjusting for preoperative opioid use, and is associated with a transient normalization of anxiety and depressive symptoms with a rebound 3 months following spine surgery. Targeted screening and risk reduction strategies are needed for patients reporting preoperative opioid misuse before spine surgery.
Objective Facet joint injections (FJIs) and medial branch blocks (MBBs) are commonly used interventions for chronic spinal pain, but their comparative effectiveness remains unclear. This meta-analysis aimed to compare the pain relief, functional improvement, complications, and patient satisfaction associated with FJI and MBB.
Methods A systematic review and meta-analysis of randomized controlled trials and observational studies were conducted. Primary outcomes included pain relief (numerical rating scale) and functional improvement (Oswestry Disability Index [ODI]/Neck Disability Index). Secondary outcomes assessed adverse effects and patient satisfaction. The differences in characteristics between patients who were readmitted and those who were not were identified and analyzed using the Review Manager software.
Results FJI resulted in lower pain and ODI scores compared to MBB, but the differences were not statistically significant. However, patient satisfaction was significantly higher in the FJI group (odds ratio, 1.81; 95% confidence interval, 1.02–3.24; p=0.04). Additionally, FJI had fewer adverse effects than MBB.
Conclusion Both FJI and MBB are effective for chronic spinal pain, but FJI may be preferred for patients seeking immediate pain relief with fewer complications. Further high-quality studies are needed to refine treatment guidelines.
Internationally, the United States (U.S.) cites the highest cost burden of low back pain (LBP). The cost continues to rise, faster than the rate of inflation and overall growth of health expenditures. We performed a comprehensive literature review of peer-reviewed and non– peer-reviewed literature from PubMed, Scopus, and Google Scholar for contemporary data on prevalence, cost, and projected future costs. Policymakers in the U.S. have long attempted to address the high-cost burden of LBP through limiting low-value services and early imaging. Despite these efforts, costs (~$40 billion; ~$2,000/patient/yr) continue to rise with increasing rates of unindicated imaging, high rates of surgery, and subsequent revision surgery without proper trial of non-pharmacologic measures and no corresponding reduction in LBP prevalence. Globally, the overall prevalence of LBP continues to rise largely secondary to a growing aging population. Cost containment methods should focus on careful and comprehensive clinical assessment of patients to better understand when more resource-intensive interventions are indicated.
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Objective Precise knowledge regarding the mechanical stress applied to the intervertebral disc following each individual spine motion enables physicians and patients to understand how people with discogenic back pain should be guided in their exercises and which spine motions to specifically avoid. We created an intervertebral disc degeneration model and conducted a finite element (FE) analysis of loaded stresses following each spinal posture or motion.
Methods A 3-dimensional FE model of intervertebral disc degeneration at L4–5 was constructed. The intervertebral disc degeneration model was created according to the modified Dallas discogram scale. The von Mises stress and range of motion (ROM) regarding the intervertebral discs and the endplates were analyzed.
Results We observed that mechanical stresses loaded onto the intervertebral discs were similar during flexion, extension, and lateral bending, which were greater than those occurring during torsion. Based on the comparison among the grades divided by the modified Dallas discogram scale, the mechanical stress during extension was greater in grades 3–5 than it was during the others. During extension, the mechanical stress loaded onto the intervertebral disc and endplate was greatest in the posterior portion. Mechanical stresses loaded onto the intervertebral disc were greater in grades 3–5 compared to those in grades 0–2.
Conclusion Our findings suggest that it might be beneficial for patients experiencing discogenic back pain to maintain a neutral posture in their lumbar spine when engaging in daily activities and exercises, especially those suffering from significant intravertebral disc degeneration.
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Objective The objective of this systematic review and meta-analysis was to assess the efficacy of exercise in neuropathic pain following traumatic spinal cord injuries.
Methods The search was conducted in MEDLINE, Embase, Scopus, and Web of Science by the end of 2022. Two independent researchers included the articles based on the inclusion and exclusion criteria. A standardized mean difference was calculated for each data and they were pooled to calculate an overall effect size. To assess the heterogeneity between studies, I2 and chi-square tests were utilized. In the case of heterogeneity, meta-regression was performed to identify the potential source.
Results Fifteen preclinical studies were included. Meta-analysis demonstrated that exercise significantly improves mechanical allodynia (standardized mean difference [SMD], -1.59; 95% confidence interval [CI], -2.16 to -1.02; p < 0.001; I2 = 90.37%), thermal hyperalgesia (SMD, 1.95; 95% CI, 0.96–2.94; p < 0.001), and cold allodynia (SMD, -2.92; 95% CI, -4.4 to -1.43; p < 0.001). The improvement in mechanical allodynia is significantly more in animals with a compression model of SCI (meta-regression coefficient, -1.33; 95% CI, -1.84 to -0.57; p < 0.001) and in mild SCI (p < 0.001). Additionally, the improvement was more prominent if the training was started 7 to 8 days postinjury (coefficient, -2.54; 95% CI, -3.85 to -1.23; p < 0.001) and was continued every day (coefficient, -1.99; 95% CI, -3.07 to -0.9; p < 0.001). Likewise, voluntary exercise demonstrated a significantly more effect size (coefficient, -1.45; 95% CI, -2.67 to -0.23; p = 0.02).
Conclusion Exercise is effective in the amelioration of neuropathic pain. This effect in mechanical allodynia is more prominent if voluntary, continuous training is initiated in the subacute phase of mild SCI.
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Objective Loss of skeletal muscle mass is known to be associated with multiple morbidities. However, there is a dearth of reports on its association with lumbar lordosis and musculoskeletal pain. The aim of this study was to delineate the cross-sectional relationship between loss of skeletal muscle mass, lumbar lordosis, and chronic low back pain (CLBP).
Methods A total of 721 medical records were reviewed, and data from 165 older subjects (over 65 years old; 81 men and 84 women) were retrospectively analyzed. Subjects were categorized into either the CLBP group (back pain for more than 6 months; 35 men and 36 women) or the control group (46 men and 48 women). The modified skeletal muscle mass index (MSMI, appendicular skeletal muscle mass [kg]/weight [kg] × 100), assessed by bioelectrical impedance analysis, and lumbar lordotic angle (LLA) were measured and compared between the CLBP group and the control group. The correlation between MSMI and LLA was investigated.
Results The LLA of men and women in the CLBP group was significantly lower than that of the control group (p < 0.05). The MSMI was decreased in the CLBP group compared to the control group (p < 0.05). For both sexes, positive correlations were observed between the MSMI and LLA.
Conclusion A close cross-sectional relationship was observed between MSMI, LLA, and CLBP. This suggests a potential interaction between the reduction in skeletal muscle mass and altered lumbar spine sagittal alignment, which could lead to CLBP.
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