Adults with excess weight or obesity, but not with overweight, report greater pain intensities than individuals with normal weight: a systematic review and meta-analysis.

Context: Over 1.9 billion adult people have overweight or obesity. Considered as a chronic disease itself, obesity is associated with several comorbidities. Chronic pain affects approximately 60 million people and its connection with obesity has been displayed in several studies. However, controversial results showing both lower and higher pain thresholds in subjects with obesity compared to individuals with normal weight and the different parameters used to define such association (e.g., pain severity, frequency or duration) make it hard to draw straight forward conclusions in the matter. The objective of this article is to examine the relationship between overweight and obesity (classified with BMI as recommended by WHO) and self-perceived pain intensity in adults. Methods: A literature search was conducted following PRISMA guidelines using the databases CINAHL, Cochrane Library, EMBASE, PEDro, PubMed, Scopus and Web of Science to identify original studies that provide BMI values and their associated pain intensity assessed by self-report scales. Self-report pain scores were normalized and pooled within meta-analyses. The Cochrane's Q test and I2 index were used to clarify the amount of heterogeneity; meta-regression was performed to explore the relationship between each outcome and the risk of bias. Results: Of 2194 studies, 31 eligible studies were identified and appraised, 22 of which provided data for a quantitative analysis. The results herein suggested that adults with excess weight (BMI ≥ 25.0) or obesity (BMI ≥ 30.0) but not with overweight (pre-obesity) alone (BMI 25.0-29.9), are more likely to report greater intensities of pain than individuals of normal weight (BMI 18.5-24.9). Subgroup analyses regarding the pathology of the patients showed no statistically significant differences between groups. Also, influence of age in the effect size, evaluated by meta-regression, was only observed in one of the four analyses. Furthermore, the robustness of the findings was supported by two different sensitivity analyses. Conclusion: Subjects with obesity and excess weight, but not overweight, reported greater pain intensities than individuals with normal weight. This finding encourages treatment of obesity as a component of pain management. More research is required to better understand the mechanisms of these differences and the clinical utility of the findings. Systematic Review Registration: https://doi.org/10.17605/OSF.IO/RF2G3, identifier OSF.IO/RF2G3.

Higher densities of T-lymphocytes in the subsynovial connective tissue of people with carpal tunnel syndrome.

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.

Effectiveness of deep dry needling versus manual therapy in the treatment of myofascial temporomandibular disorders: a systematic review and network meta-analysis.

BACKGROUND: Temporomandibular disorders (TMDs) are the most common cause of orofacial pain of non-dental origin, with approximately 42% of diagnoses corresponding to myofascial pain. Manual therapy and dry needling are commonly used interventions for the treatment of myofascial temporomandibular disorders. However, it is unclear whether one of them could be superior to the other. OBJECTIVES: The aim of the present systematic review and network meta-analysis was to compare the effectiveness of manual therapy and dry needling in patients with myofascial TMD. METHODS: This is a systematic review and network meta-analysis. Randomized clinical trials were searched in the databases of Pubmed, PEDro, CINAHL, Web of Science, Scopus, Cochrane, Google Academic and EMBASE. The methodological quality of studies included in this review was judged using the Physiotherapy Evidence Database (PEDro) scale. A frequentist network meta-analysis was carried out, assuming random effects, to estimate the effects of interventions for temporomandibular joint pain measured on a 10-point visual analogue scale. RESULTS: Out of 3190 records identified, 17 met the inclusion criteria for qualitative analysis and eight were included in the network meta-analysis. Indirect comparisons between dry needling and manual therapy showed no significant differences in their effects on pain reduction (Odds Ratio [95%CI]; - 0.263 [- 1.517, 0.992]). The ranking of treatments shows that manual therapy (SUCRA = 0.932) followed by deep dry needling (SUCRA = 0.775) present the highest values of estimation and can be considered the most likely to reduce pain. CONCLUSIONS: The results of the network meta-analysis should be considered with caution due to the low quality of the evidence available and the high variability of the study protocols in terms of the method of application of dry needling and manual therapy interventions. PROSPERO under identifier: (CRD42020186470).

Conditioned pain modulation and psychological factors in young adults with recurrent or chronic neck pain.

BACKGROUND: Controversy exists with the presence of alterations in descending pain inhibition mechanisms in patients with non-specific neck pain (NSNP). The aim of the present study was to evaluate the status of conditioned pain modulation CPM, remote pressure pain thresholds (PPT), and psychological factors in a specific subgroup of patients with NSNP such as young adult students. In addition, possible associations between CPM, psychological factors, and pain characteristics were analyzed. METHODS: Thirty students with recurrent or chronic NSNP and 30 pain-free students were included in this cross-sectional study. The following measures were assessed: CPM, remote PPT, psychological factors (depression, anxiety, pain catastrophizing, and kinesiophobia), pain characteristics (duration, intensity, severity of chronic pain, interference with daily life), and central sensitization inventory (CSI). RESULTS: No significant differences were found in the efficacy of CPM between students with chronic or recurrent NSNP and pain-free students (ß coefficient = -0.67; 95% CI = -1.54, 0.20). However, students with pain showed a significantly higher remote PPT (mean difference = -1.94; 95% CI = -2.71, -1.18). and a greater presence of anxious (mean difference = 6; 95% CI = 2, 9) and depressive symptoms (mean difference = 8.57; 95% CI = 3.97, 13.16). In addition, significant moderate or strong correlations were found between CPM and pain intensity (partial r = 0.41), pain catastrophizing and mean pain intensity (r = 0.37), grade (r = 0.50), and interference of pain (r = 0.57), kinesiophobia and disability (r = 0.38), and depression and CSI (r = 0.39). CONCLUSIONS: Young adult students with chronic or recurrent NSNP present remote hyperalgesia and symptoms of depression and anxiety but not dysfunctional CPM.

Reply to Rossettini et al. "Do Not Mix Apples with Oranges" to Avoid Misinterpretation of Placebo Effects in Manual Therapy: The Risk Is Resulting in a Fruit Basket. Comment on "Molina-Álvarez et al. Manual Therapy Effect in Placebo-Controlled Trials: A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health 2022, 19, 14021".

We have thoroughly reviewed and carefully analyzed the points raised in the comment titled: "Do not mix apples with oranges" to avoid misinterpretation of placebo effects in manual therapy: the risk is resulting in a fruit basket [...].

Manual Therapy Effects on Nonspecific Neck Pain Are Not Mediated by Mechanisms Related to Conditioned Pain Modulation: A Randomized Clinical Trial.

BACKGROUND: Manual therapy (MT) is a treatment recommended by clinical practice guidelines in the management of patients with neck pain. However, the mechanisms through which MT works remain unknown. The aim of the present study is to investigate if MT is mediated by mechanisms related to conditioned pain modulation (CPM), comparing the effects of painful with a pain-free MT treatment. METHODS: A two-arm, parallel, randomized controlled clinical trial with concealed allocation and blinding of the outcome assessor was conducted in university students with chronic or recurrent nonspecific neck pain (NSNP). Participants received either a painful or pain-free MT session. Psychophysical variables including pressure pain thresholds, CPM, temporal summation of pain and cold pain intensity were assessed before and immediately after treatment. In addition, changes in neck pain intensity over the following 7 days and self-perceived improvement immediately and 7 days after treatment were assessed. RESULTS: No significant differences were found between groups in any of the psychophysical variables or in patients' self-perceived improvement. Only a significantly greater decrease in neck pain intensity immediately after treatment was found in the pain-free MT group compared to the painful MT group. CONCLUSION: The results suggest that the immediate and short-term effects of MT on NSNP are not mediated by CPM-related mechanisms.

Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies: A Systematic Review and Meta-analysis.

Importance: 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. Objective: To assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants. Data Sources: Ovid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021. Study Selection: 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 Extraction and Synthesis: 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. Main Outcomes and Measures: The outcome of interest was concentration of biomarkers. Results: 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. Conclusions and Relevance: 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.

Manual Therapy Effect in Placebo-Controlled Trials: A Systematic Review and Meta-Analysis.

PURPOSE: Background: Evaluate whether the design of placebo control groups could produce different interpretations of the efficacy of manual therapy techniques. METHODS: Nine databases were searched (EMBASE, CINAHL, PsycINFO, MEDLINE, PubMed, SCOPUS, WEB of SCIENCE, COCHRANE, and PEDro). Randomized placebo-controlled clinical trials that used manual therapy as a sham treatment on subjects suffering from pain were included. Data were summarized qualitatively, and meta-analyses were conducted with R. RESULTS: 53 articles were included in the qualitative analysis and 48 were included in the quantitative analyses. Manipulation techniques did not show higher effectiveness when compared with all types of sham groups that were analyzed (SMD 0.28; 95%CI [-0.24; 0.80]) (SMD 0.28; 95%CI [-0.08; 0.64]) (SMD 0.42; 95%CI [0.16; 0.67]) (SMD 0.82; 95%CI [-0.57; 2.21]), raising doubts on their therapeutic effect. Factors such as expectations of treatment were not consistently evaluated, and analysis could help clarify the effect of different sham groups. As for soft tissue techniques, the results are stronger in favor of these techniques when compared to sham control groups (SMD 0.40; 95%CI [0.19, 0.61]). Regarding mobilization techniques and neural gliding techniques, not enough studies were found for conclusions to be made. CONCLUSIONS: The literature presents a lack of a unified placebo control group design for each technique and an absence of assessment of expectations. These two issues might account for the unclear results obtained in the analysis.

Antinociceptive and modulatory effect of pathoplastic changes in spinal glia of a TLR4/CD14 blocking molecule in two models of pain in rat.

The role of spinal glia in the development and maintenance of chronic pain has become over the last years a subject of increasing interest. In this regard, toll-like receptor 4 (TLR4) signaling has been proposed as a major trigger mechanism. Hence, in this study we explored the implications of TLR4 inhibition in the periphery and primarily in the CNS, focusing on the impact this inhibition renders in pain development and glia activation in the dorsal horn in two models of pain. Making use of a synthetic cluster of differentiation 14 (CD14)/TLR4 antagonist, the effect of TLR4 blockade on tactile allodynia and heat hyperalgesia was evaluated in osteoarthritic and postoperative rat models. An in vitro parallel artificial membrane permeation assay was performed to determine the proneness of the drug to permeate the blood-brain barrier prior to systemic and central administration. Findings suggest a dominant role of peripheral TLR4 in the model of incisional pain, whilst both peripheral and central TLR4 seem to be responsible for osteoarthritic pain. That is, central and peripheral TLR4 may be differently involved in the etiopathology of diverse types of pain what potentially seems a promising approach in the management of pain.

Clusterin: Always protecting. Synthesis, function and potential issues.

In the last years, clusterin, a challenging and paradoxical apolipoprotein, has been of growing interest amongst a rising number of scientists. This enigmatic protein is present in all fluids of the organism besides within the intracellular matrix, and it plays diverse, and at times contrary, roles in a growing number of pathologies. It seems to vary its location and function to assure cellular survival being cytoprotective hence its significance in neuroprotection and cancer along with chemotherapy resistance. However, it can also lead to cellular arrest and its modulation to apoptosis. Additionally, it has been described to modulate pain, as well as linked to inflammation, cardioprotection, satiety and hunger, and possibly to addictive behaviour development. Thus, it has been postulated to be used both as a biomarker and a very explorable new therapeutic target for several conditions.

Toll-like receptor 4: A promising crossroads in the diagnosis and treatment of several pathologies.

Toll-like receptor 4 (TLR4) is expressed in a wide variety of cells and is the central component of the mammalian innate immune system. Since its discovery in 1997, TLR4 has been assigned an ever-increasing number of functions that extend from pathogen recognition to tissue damage identification and promotion of the intrinsic "damage repair response" in pain, intestinal, respiratory and vascular disorders. Precisely, the finding of conserved sequence homology among species along with the molecular and functional characterisation of the TLR4 gene enabled researchers to envisage a common operating system in the activation of innate immunity and the initiation of plastic changes at the onset of chronic pain. Malfunctioning in other conditions was conceived in parallel. In this respect, "pivot" proteins and pathway redundancy are not just evolutionary leftovers but essential for normal functioning or cell survival. Indeed, at present, TLR4 single nucleotide polymorphisms (SNP) and their association with certain dysfunctions and diseases are being confirmed in different pools of patients. However, despite its ability to trigger pathogen infection or alternatively tissue injury communications to immune system, TLR4 targeting might not be considered a panacea. This review article represents a compilation of what we know about TLR4 from clinics and basic research on the 20th anniversary of its discovery. Understanding how to fine-tune the interaction between TLR4 and its specific ligands may lead in the next decades to the development of promising new treatments, reducing polypharmacy and probably having an impact on drug use in numerous pathologies.