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Highly variable pain mechanisms in people with low back pain or spine-related leg pain might contribute to inefficacy of neuropathic pain medication. This meta-analysis aimed to determine how neuropathic pain is identified in clinical trials for people taking neuropathic pain medication for low back pain or spine-related leg pain and whether subgrouping based on the presence of neuropathic pain influences efficacy. EMBASE, MEDLINE, Cochrane Central, CINAHL [EBSCO], APA PsycINFO, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry were searched from inception to 14 May, 2024. Randomized and crossover trials comparing first-line neuropathic pain medication for people with low back pain or spine-related leg pain to placebo or usual care were included. Two independent authors extracted data. Random-effects meta-analyses of all studies combined, and pre-planned subgroup meta-analyses based on the certainty of neuropathic pain (according to the neuropathic pain Special Interest Group [NeuPSIG] neuropathic pain grading criteria) were completed. Certainty of evidence was judged using the grading of recommendations assessment development and evaluation [GRADE] framework. Twenty-seven included studies reported on 3619 participants. Overall, 33% of studies were judged unlikely to include people with neuropathic pain, 26% remained unclear. Only 41% identified people with possible, probable, or definite neuropathic pain. For pain, general analyses revealed only small effects at short term (mean difference [MD] - 9.30 [95% confidence interval [CI] - 13.71, - 4.88], I = 87%) and medium term (MD - 5.49 [95% CI - 7.24, - 3.74], I = 0%). Subgrouping at short term revealed studies including people with definite or probable neuropathic pain showed larger effects on pain (definite; MD - 16.65 [95% CI - 35.95, 2.65], I = 84%; probable; MD - 10.45 [95% CI - 14.79, - 6.12], I = 20%) than studies including people with possible (MD - 5.50 [95% CI - 20.52, 9.52], I = 78%), unlikely (MD - 6.67 [95% CI - 10.58, 2.76], I = 0%), or unclear neuropathic pain (MD - 8.93 [95% CI - 20.57, 2.71], I = 96%). Similarly, general analyses revealed negligible effects on disability at short term (MD - 3.35 [95% CI - 9.00, 2.29], I = 93%) and medium term (MD - 4.06 [95% CI - 5.63, - 2.48], I = 0%). Sub-grouping at short term revealed larger effects in studies including people with definite/probable neuropathic pain (MD - 9.25 [95% CI - 12.59, - 5.90], I = 2%) compared with those with possible/unclear/unlikely neuropathic pain (MD -1.57 [95% CI - 8.96, 5.82] I = 95%). Medium-term outcomes showed a similar trend, but were limited by low numbers of studies. Certainty of evidence was low to very low for all outcomes. Most studies using neuropathic pain medication for low back pain or spine-related leg pain fail to adequately consider the presence of neuropathic pain. Meta-analyses suggest neuropathic pain medication may be most effective in people with low back pain or spine-related leg pain with a definite/probable neuropathic pain component. However, the low to very low certainty of evidence and poor identification of neuropathic pain in most studies prevent firm recommendations.

PurposePhysiotherapy interventions are prescribed as first-line treatment for people with sciatica; however, their effectiveness remains controversial. The purpose of this systematic review was to establish the short-, medium- and long-term effectiveness of physiotherapy interventions compared to control interventions for people with clinically diagnosed sciatica.MethodsThis systematic review was registered on PROSPERO CRD42018103900. Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), Embase, PEDro, PubMed, Scopus and grey literature were searched from inception to January 2021 without language restrictions. Inclusion criteria were randomised controlled trials evaluating physiotherapy interventions compared to a control intervention in people with clinical or imaging diagnosis of sciatica. Primary outcome measures were pain and disability. Study selection and data extraction were performed by two independent reviewers with consensus reached by discussion or third-party arbitration if required. Risk of bias was assessed independently by two reviewers using the Cochrane Risk of Bias tool with third-party consensus if required. Meta-analyses and sensitivity analyses were performed with random effects models using Revman v5.4. Subgroup analyses were undertaken to examine the effectiveness of physiotherapy interventions compared to minimal (e.g. advice only) or substantial control interventions (e.g. surgery).ResultsThree thousand nine hundred and fifty eight records were identified, of which 18 trials were included, with a total number of 2699 participants. All trials had a high or unclear risk of bias. Meta-analysis of trials for the outcome of pain showed no difference in the short (SMD − 0.34 [95%CI − 1.05, 0.37] p = 0.34, I2 = 98%), medium (SMD 0.15 [95%CI − 0.09, 0.38], p = 0.22, I2 = 80%) or long term (SMD 0.09 [95%CI − 0.18, 0.36], p = 0.51, I2 = 82%). For disability there was no difference in the short (SMD − 0.00 [95%CI − 0.36, 0.35], p = 0.98, I2 = 92%, medium (SMD 0.25 [95%CI − 0.04, 0.55] p = 0.09, I2 = 87%), or long term (SMD 0.26 [95%CI − 0.16, 0.68] p = 0.22, I2 = 92%) between physiotherapy and control interventions. Subgroup analysis of studies comparing physiotherapy with minimal intervention favoured physiotherapy for pain at the long-term time points. Large confidence intervals and high heterogeneity indicate substantial uncertainly surrounding these estimates. Many trials evaluating physiotherapy intervention compared to substantial intervention did not use contemporary physiotherapy interventions.ConclusionBased on currently available, mostly high risk of bias and highly heterogeneous data, there is inadequate evidence to make clinical recommendations on the effectiveness of physiotherapy interventions for people with clinically diagnosed sciatica. Future studies should aim to reduce clinical heterogeneity and to use contemporary physiotherapy interventions.

Preliminary evidence from studies using quantitative sensory testing suggests the presence of central mechanisms in patients with carpal tunnel syndrome (CTS) as apparent by widespread hyperalgesia. Hallmarks of central mechanisms after nerve injuries include nociceptive facilitation and reduced endogenous pain inhibition. Methods to study nociceptive facilitation in CTS so far have been limited to quantitative sensory testing and the integrity of endogenous inhibition remains unexamined. The aim of this study was therefore to investigate changes in facilitatory and inhibitory processing in patients with CTS by studying hypersensitivity following experimentally induced pain (facilitatory mechanisms) and the efficacy of conditioned pain modulation (CPM, inhibitory mechanisms). Twenty-five patients with mild to moderate CTS and 25 age and sex matched control participants without CTS were recruited. Increased pain facilitation was evaluated via injection of hypertonic saline into the upper trapezius. Altered pain inhibition through CPM was investigated through cold water immersion of the foot as the conditioning stimulus and pressure pain threshold over the thenar and hypothenar eminence bilaterally as the test stimulus. The results demonstrated that patients with CTS showed a greater duration (p = 0.047), intensity (p = 0.044) and area (p = 0.012) of pain in response to experimentally induced pain in the upper trapezius and impaired CPM compared to the control participants (p = 0.006). Although typically considered to be driven by peripheral mechanisms, these findings indicate that CTS demonstrates characteristics of altered central processing with increased pain facilitation and reduced endogenous pain inhibition.

Purpose To establish the prevalence and agreement between reported and observed leg weakness in people with sciatica. To establish which factors mediate any identified difference between reported and observed leg weakness in people with sciatica. Methods 68 people with a clinical diagnosis of sciatica, records from spinal service, secondary care NHS Hospital, England, UK reviewed. Primary outcome measures were the sciatica bothersome index for reported leg weakness and the Medical Research Council scale for observed weakness. Agreement was established with Cohen’s Kappa and intraclass correlation coefficient. Potential factors that may mediate a difference between reported and observed weakness included leg pain, sciatica bothersome index sensory subscale, age, hospital anxiety and depression subscale for anxiety. Results 85% of patients reported weakness but only 34% had observed weakness. Cohen’s Kappa (0.066, 95% CI − 0.53, 0.186; p  = 0.317)] and ICC 0.213 (95% CI − 0.26, 0.428, p  = 0.040) both showed poor agreement between reported and observed weakness. The difference between reported and observed measures of weakness was mediated by the severity of leg pain (b = 0.281, p  = 0.024) and age (b = 0.253, p  = 0.042). Conclusion There is a high prevalence of reported leg weakness in people with sciatica, which is not reflected in observed clinical measures of weakness. Differences between reported and observed weakness may be driven by the severity of leg pain and age. Further work needs to establish whether other objective measures can detect patient reported weakness.

Symptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as “non-inflammatory” based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.

Carpal tunnel syndrome (CTS) is a common and disabling condition of the hand caused by entrapment of the median nerve at the level of the wrist. It is the commonest entrapment neuropathy, with estimates of prevalence ranging between 5–10%. Here, we undertake a genome-wide association study (GWAS) of an entrapment neuropathy, using 12,312 CTS cases and 389,344 controls identified in UK Biobank. We discover 16 susceptibility loci for CTS with p < 5 × 10 −8 . We identify likely causal genes in the pathogenesis of CTS, including ADAMTS17 , ADAMTS10 and EFEMP1 , and using RNA sequencing demonstrate expression of these genes in surgically resected tenosynovium from CTS patients. We perform Mendelian randomisation and demonstrate a causal relationship between short stature and higher risk of CTS. We suggest that variants within genes implicated in growth and extracellular matrix architecture contribute to the genetic predisposition to CTS by altering the environment through which the median nerve transits. Carpal tunnel syndrome (CTS) is caused by entrapment of the median nerve at the wrist. Here, Wiberg et al. perform a GWAS for CTS in the UK Biobank cohort and identify 16 genetic loci, and find a causal relationship between short stature and CTS risk using Mendelian randomisation.

Background To diagnose cervical radiculopathy according to the International Association for the Study of Pain definition, signs of neurological deficits must be examined with the neurological examination. However, the diagnostic accuracy of the standard neurological examination remains unclear, and no clear recommendations exist about standard components. Therefore, the objectives of this review are to map the research about the diagnostic accuracy, components, and performance of the neurological examination for cervical radiculopathy. Method PubMed, Embase, Scopus, Cinhal, DiTA databases were searched up to February 23rd, 2024. Additional studies were identified through screening reference lists of the included studies. Studies on neurological examination procedures and their diagnostic accuracy for cervical radiculopathy were included. Results From an initial 12,365 records, 6 articles met the inclusion criteria. All articles were cross-sectional studies and compared the neurological examination with electrodiagnostic tests or magnetic resonance imaging. Reduced tendon reflexes were found to be most specific (81% (95% CI 69–89%) to 99% (95% CI not reported)), while somatosensation testing was least sensitive (25% (95% CI 12–38%; -LR 0.84) to 52% (95% CI 30–74%)). Taking all components into account resulted in higher specificity (98% (95% CI not reported) to 99% (95% CI 95–100%)) but lower sensitivity (7% (95% CI not reported) to 14% (95% CI 5–16%)) compared to electrodiagnostic tests. Conclusions We found varying operational definitions of radiculopathy, suboptimal reference standards, and great heterogeneity in the neurological examination procedure and its diagnostic accuracy. Future research should address these issues to establish the clinical utility of the neurological examination for cervical radiculopathy. Protocol https://doi.org/10.1101/2023.05.22.23290194 . Key messages What is already known about this topic According to the International Association for the Study of Pain, cervical radiculopathy is defined by neurological deficit which can be probed by a bedside neurological examination. Little is known about its diagnostic accuracy and procedure. What does the study add There is heterogeneity in the neurological examination procedure, the reference standards (e.g., electrophysiology and diagnostic imaging), and its diagnostic accuracy. Components of the neurological examination for cervical radiculopathy have high specificity but low sensitivity.

PurposeProprioceptive deficits are common in low back pain. The multifidus muscle undergoes substantial structural change after back injury, but whether muscle spindles are affected is unclear. This study investigated whether muscle spindles of the multifidus muscle are changed by intervertebral disc (IVD) degeneration in a large animal model.MethodsIVD degeneration was induced by partial thickness annulus fibrosus lesion to the L3-4 IVD in nine sheep. Multifidus muscle tissue at L4 was harvested at six months after lesion, and from six age-/sex-matched naïve control animals. Muscle spindles were identified in Van Gieson’s-stained sections by morphology. The number, location and cross-sectional area (CSA) of spindles, the number, type and CSA of intrafusal fibers, and thickness of the spindle capsule were measured. Immunofluorescence assays examined Collagen I and III expression.ResultsMultifidus muscle spindles were located centrally in the muscle and generally near connective tissue. There were no differences in the number or location of muscle spindles after IVD degeneration and only changes in the CSA of nuclear chain fibers. The thickness of connective tissue surrounding the muscle spindle was increased as was the expression of Collagen I and III.ConclusionChanges to the connective tissue and collagen expression of the muscle spindle capsule are likely to impact their mechanical properties. Changes in capsule stiffness may impact the transmission of length change to muscle spindles and thus transduction of sensory information. This change in muscle spindle structure may explain some of the proprioceptive deficits identified with low back pain.

PurposeIntervertebral disk (IVD) lesion and its subsequent degeneration have a profound effect on the multifidus muscle. The subacute/early chronic phase of multifidus remodeling after IVD lesion has been proposed to be regulated by inflammatory processes. The balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages plays an important role in maintaining tissue integrity after injury. The localization, polarization of macrophage subtypes and their mediation of the pro-inflammatory cytokine tumor necrosis factor (TNF) are unknown in paraspinal muscles during IVD degeneration. A sheep model of IVD degeneration was used to investigate the role of macrophages and TNF in the structural alterations that occur within the multifidus muscle.MethodsAnterolateral lesions were induced at L3–4 IVD in sheep. Multifidus muscle tissue at L4 was harvested 3 and 6 months after lesion and used for immunofluorescence assays to examine total macrophage number, macrophage polarization between M1 and M2, and to assess the localization of TNF expression in muscle, adipose and connective tissues from injured and naïve control animals.ResultsA greater proportion of M1 macrophages is present in muscle at both 3 and 6 months after IVD lesion, and adipose tissue at 6 months. Total number of macrophages is unchanged. At 6 months, expression of TNF is increased in adipose and connective tissue and the proportion of TNF expressed by M1 macrophages is increased.ConclusionsThese data support the proposal that macrophages and TNF (pro-inflammatory cytokine) play an active role in the subacute/early chronic phase of remodeling in muscle, adipose and connective tissues of the multifidus during IVD degeneration. This presents a novel target for treatment.Graphical abstractThese slides can be retrieved under Electronic Supplementary Material.

Peripheral neuropathies are common conditions and can result in numbness, paresthesia, motor deficits, and pain. There is increasing evidence for the use of biomarkers as clinical indicators of the presence, severity, and prognosis of nerve lesions; however, biomarker identification has largely been focused on disorders of the central nervous system, and less is known about their role in the peripheral nervous system. To assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants. Ovid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021. Observational studies reporting on blood biomarkers in patients diagnosed with peripheral neuropathy were included. This review was preregistered on PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were abstracted by 1 investigator and independently reviewed by a second. Data were meta-analyzed when at least 2 studies reported the same biomarker with comparable methodology. Fixed-effects models were used when only 2 studies were included; random-effects models were used when more than 2 studies were included. The outcome of interest was concentration of biomarkers. This review included 36 studies reporting on 4414 participants, including 2113 control participants and 2301 patients with peripheral neuropathy with 13 distinct peripheral neuropathy diagnoses. Diabetic neuropathy was the most common neuropathy diagnosis (13 studies), followed by Charcot-Marie-Tooth disease (6 studies) and Guillain-Barre syndrome (6 studies). Overall, 16 different blood-based biomarkers associated with nerve involvement were evaluated. The most used were neurofilament light chain, S100B, brain-derived neurotrophic factor, and neuron-specific enolase. Patients with peripheral neuropathy demonstrated significantly higher levels of neurofilament light chain compared with controls (standardized mean difference [SMD], 0.93 [95% CI, 0.82 to 1.05]; P < .001). There were no significant differences in levels of S100B (SMD, 1.10 [95% CI, -3.08 to 5.28]; P = .38), brain-derived neurotrophic factor (SMD, -0.52 [95% CI, -2.23 to 1.19]; P = .40), or neuron-specific enolase (SMD, -0.00 [95% CI, -1.99 to 1.98]; P = .10) in patients with peripheral neuropathy compared with control participants. The findings of this systematic review and meta-analysis support the use of neurofilament light chain as a blood-based measure associated with the presence of neuronal injury in patients with peripheral neuropathy.