Associations between Vitamin D, Omega 6:Omega 3 Ratio, and Biomarkers of Aging in Individuals Living with and without Chronic Pain.

Elevated inflammatory cytokines and chronic pain are associated with shorter leukocyte telomere length (LTL), a measure of cellular aging. Micronutrients, such as 25-hydroxyvitamin D (vitamin D) and omega 3, have anti-inflammatory properties. Little is known regarding the relationships between vitamin D, omega 6:3 ratio, LTL, inflammation, and chronic pain. We investigate associations between vitamin D, omega 6:3 ratio, LTL, and C-reactive protein (CRP) in people living with/without chronic pain overall and stratified by chronic pain status. A cross-sectional analysis of 402 individuals (63% women, 79.5% with chronic pain) was completed. Demographic and health information was collected. Chronic pain was assessed as pain experienced for at least three months. LTL was measured in genomic DNA isolated from blood leukocytes, and micronutrients and CRP were measured in serum samples. Data were analyzed with general linear regression. Although an association between the continuous micronutrients and LTL was not observed, a positive association between omega 6:3 ratio and CRP was detected. In individuals with chronic pain, based on clinical categories, significant associations between vitamin D, omega 6:3 ratio, and CRP were observed. Findings highlight the complex relationships between anti-inflammatory micronutrients, inflammation, cellular aging, and chronic pain.

Effect of neurogenic acupoint cupping on high sensitive C-reactive protein and pain perception in female chronic pelvic pain: A randomized controlled trial.

OBJECTIVES: To determine the effect of neurogenic acupoint dry cupping therapy on high sensitive C-reactive protein (hs-CRP) level, pain perception & intensity, and life impact of pelvic pain in women with chronic pelvic pain (CPP), with regard to the biological and neurophysiological impacts of dry cupping on acupoint. METHODS: Thirty women with CPP were randomly divided into two equal groups; the study group received dry cupping on neurogenic acupoints plus lifestyle modifications for 8 weeks (n=15), while the control group received only lifestyle modifications for 8 weeks (n=15). Women were assessed pre- and post-rehabilitation program with the hs-CRP blood test, the short-form McGill Pain Questionnaire (SF-MPQ), and the pelvic pain impact questionnaire (PPIQ). RESULTS: Comparing both groups post-treatment revealed that there were significant reductions in levels of hs-CRP, and scores of SF-MPQ & PPIQ (p<0.05) in the study group compared with the control group. Also, there were significant positive correlations between hs-CRP and both SF-MPQ "Visual Analogue Scale (VAS), Present Pain Intensity (PPI) index & Pain Rating Index (PRI)" and PPIQ (p<0.05). CONCLUSION: Neurogenic acupoint cupping therapy had significantly improving effects on the degree of inflammation, pain perception & intensity, and life impact of pelvic pain in women with CPP.

Spa therapy induces clinical improvement and protein changes in patients with chronic back pain.

This study is primarily aimed at assessing serum changes on a large panel of proteins in patients with chronic back pain following spa therapy, as well as evaluating different spa therapy regimens as a preliminary exploratory clinical study. Sixty-six patients with chronic back pain secondary to osteoarthritis were randomly enrolled and treated with daily mud packs and bicarbonate-alkaline mineral water baths, or a thermal hydrotherapy rehabilitation scheme, the combination of the two regimens or usual medication only (control group), for two weeks. Clinical variables were evaluated at baseline, after 2 and 12 weeks. One thousand serum proteins were tested before and after a two-week mud bath therapy. All spa treatment groups showed clinical benefit as determined by improvements in VAS pain, Roland Morris disability questionnaire and neck disability index at both time points. The following serum proteins were found greatly increased (≥2.5 fold) after spa treatment: inhibin beta A subunit (INHBA), activin A receptor type 2B (ACVR2B), angiopoietin-1 (ANGPT1), beta-2-microglobulin (B2M), growth differentiation factor 10 (GDF10), C-X-C motif chemokine ligand 5 (CXCL5), fibroblast growth factor 2 (FGF2), fibroblast growth factor 12 (FGF12), oxidized low density lipoprotein receptor 1 (OLR1), matrix metallopeptidase 13 (MMP13). Three proteins were found greatly decreased (≤0.65 fold): apolipoprotein C-III (Apoc3), interleukin 23 alpha subunit p19 (IL23A) and syndecan-1 (SDC1). Spa therapy was confirmed as beneficial for chronic back pain and proved to induce changes in proteins involved in functions such as gene expression modulation, differentiation, angiogenesis, tissue repair, acute and chronic inflammatory response.

Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling.

BACKGROUND: In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. METHODS: Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER™ pathway enrichment analysis tool. RESULTS: Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. CONCLUSIONS: In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.

The association between chronic musculoskeletal pain and clinical outcome in chronic kidney disease patients: a prospective cohort study.

BACKGROUND AND OBJECTIVES: Chronic musculoskeletal (MS) pain is common in chronic kidney disease (CKD) patients. The association of chronic MS pain and CKD progression has not yet been established. METHOD: We conducted a prospective cohort study to evaluate the association of chronic MS pain and CKD progression of pre-dialysis CKD patients. RESULT: A total of 53.2% of pre-dialysis CKD patients had chronic MS pain. Patients classified as progression and non-progression had a similar prevalence of chronic MS pain at baseline, and similar baseline use of NSAIDs and Chinese herbal medicines. Univariate Cox analysis indicated that chronic MS pain and baseline NSAID or Chinese herbal medicine use were not significantly associated with progression of CKD. But multivariate Cox regression found chronic MS pain was independently significantly associated with all-cause mortality (HR, 2.912, 95% CI, 1.004-8.444; p = .049). However, serum levels of hs-CRP were similar between those chronic MS pain patients and without chronic MS pain patients (4.96 ± 9.4 vs. 4.25 ± 13.3 mg/L, p = .535). CONCLUSION: The CKD patients with chronic MS pain was independently and significantly associated with all-cause mortality, but not independently and significantly associated with CKD progression and composite endpoints. The inflammatory marker-hs-CRP was similar between CKD patients with and without chronic MS pain.

Association between serum 25-hydroxyvitamin D levels and self-reported chronic pain in older adults: A cross-sectional analysis from the ViDA study.

Chronic pain is a major contributor to the global burden of disability. Prior studies on the association between serum 25-hydroxyvitamin D (25(OH)D) levels and chronic pain have yielded mixed results. The Vitamin D Assessment study, a large randomized controlled trial from New Zealand, offered the opportunity to examine this association in data collected at baseline in all participants, and among those with arthritis or depression. A total of 5110 participants aged 50-84 years were recruited from community general practices. Chronic pain (lasting ≥6 months) and other baseline characteristics were collected at baseline interview. Serum 25(OH)D concentration was measured by liquid chromatography-tandem mass spectrometry. Associations between 25(OH)D levels and chronic pain were explored using multivariable log-binomial regression to estimate relative risks (RRs). Out of 5049 participants with complete data, 871 (17%) reported having this clinical outcome, and 1254 (25%) had a 25(OH)D concentration <50 nmol/L. There was no significant association between 25(OH)D and chronic pain, with vitamin D status categorized in four groups: <25.0, 25.0-49.9, 50.0-74.9, and ≥75.0 nmol/L (the highest group as reference). The unadjusted RRs were 1.09, 1.10, and 1.08, respectively (Ptrend = 0.24). Adjustment for demographics, lifestyle, BMI, medical history, prescription of analgesics and vitamin D supplements did not change this finding. Similar non-significant results were observed in participants with arthritis (n = 1732) or depression (n = 528). In this multi-ethnic, community-selected sample of older adults in New Zealand, serum 25(OH)D levels were not associated with chronic pain. These results do not support a role for low vitamin D status in the prevalence of chronic pain in older adults.

Metabolomic markers of fatigue: Association between circulating metabolome and fatigue in women with chronic widespread pain.

BACKGROUND: Fatigue is a sensation of unbearable tiredness that frequently accompanies chronic widespread musculoskeletal pain (CWP) and inflammatory joint disease. Its mechanisms are poorly understood and there is a lack of effective biomarkers for diagnosis and onset prediction. We studied the circulating metabolome in a population sample characterised for CWP to identify biomarkers showing specificity for fatigue. MATERIAL AND METHODS: Untargeted metabolomic profiling was conducted on fasting plasma and serum samples of 1106 females with and without CWP from the TwinsUK cohort. Linear mixed-effects models accounting for covariates were used to determine relationships between fatigue and metabolites. Receiver operating curve (ROC)-analysis was used to determine predictive value of metabolites for fatigue. RESULTS: While no association between fatigue and metabolites was identified in twins without CWP (n=711), in participants with CWP (n=395), levels of eicosapentaenoate (EPA) ω-3 fatty acid were significantly reduced in those with fatigue (ß=-0.452±0.116; p=1.2×10-4). A significant association between fatigue and two other metabolites also emerged when BMI was excluded from the model: 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and C-glycosyltryptophan (p=1.5×10-4 and p=3.1×10-4, respectively). ROC analysis has identified a combination of 15 circulating metabolites with good predictive potential for fatigue in CWP (AUC=75%; 95% CI 69-80%). CONCLUSION: The results of this agnostic metabolomics screening show that fatigue is metabolically distinct from CWP, and is associated with a decrease in circulating levels of EPA. Our panel of circulating metabolites provides the starting point for a diagnostic test for fatigue in CWP.

Therapeutic effects of Qian-Yu decoction and its three extracts on carrageenan-induced chronic prostatitis/chronic pelvic pain syndrome in rats.

BACKGROUND: Qian-Yu decoction (QYD) is a traditional Chinese medicinal recipe composed of Radix astragali (Astragalus membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P.K. Hsiao, Fabaceae ), Herba epimedii (Epimedium brevicornum Maxim., Berberidaceae), Herba leonuri (Leonurus japonicus Houtt., Lamiaceae), Cortex phellodendri (Phellodendron chinense Schneid., Rutaceae) and Radix achyranthis bidentatae (Achyranthes bidentata Bl., Amaranthaceae). This study aimed to evaluate the therapeutic activity of QYD against carrageenan-induced chronic prostatic/chronic pelvic pain syndrome (CP/CPPS) in rats and further elucidate its effective components. METHODS: Three types of components, total polysaccharides, total flavonoids and total saponins were separately extracted from QYD. Carrageenan-induced CP/CPPS rats were intragastrically administered with lyophilized product of QYD, individual extracts and all the combined forms of extracts for three weeks. Prostatic index (PI) was determined and histopathological analysis was performed. The levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), cyclooxygenase-2 (COX-2) and prostaglandin E2 (PEG2) in rat prostate tissues were measured using ELISA. The production of inducible nitric oxide synthase (iNOS) was evaluated by an enzymatic activity assay, and the release of nitric oxide (NO) was determined by a nitrate/nitrite assay. RESULTS: Treatment with QYD significantly ameliorated the histological changes of CP/CPPS rats and reduced the PI by 44.3%, with a marked downregulation of TNF-α (42.8% reduction), IL-1ß (45.3%), COX-2 (36.6%), PGE2 (44.2%), iNOS (54.1%) and NO (46.0%). Each of three extracts attenuated the symptom of CP/CPPS, but much more weakly than QYD. The combined administration of three extracts showed efficacy comparable to that of QYD while better than that of any combination of two extracts. A principal component analysis of the six inflammatory mediators as variables indicated that the effects of TS on CP/CPPS were rather different from those of TF and TP, which were similar. CONCLUSIONS: QYD can be beneficial in prevention and treatment of CP/CPPS. Polysaccharides, flavonoids and saponins, as the major effective components of QYD, exert a cooperative effect on CP/CPPS.

The effects of black soybean (Glycine max var.) on chronic cervical pain of sedentary office workers in a northern Chinese population.

Chronic cervical pain is a common symptom of sedentary office workers. Black soybean (Glycine max var.) has rich necessary nutrients for the therapy of chronic pain. Thus, it may ease chronic cervical pain. To prove our claim, 260 sedentary office workers with chronic pain were recruited and they consumed the defined diets at breakfast, lunch, and dinner with 1 g, 5 g and 10 g (3 g, 15 g, 30 g daily) cooked black soybean for 24 weeks. Visual analog scale (VAS), neck disability index (NDI) pain scores and short-form 36 (SF-36) health survey questionnaires were applied in the study. The levels of N-methyl-D-aspartate receptors (NMDAR) were measured. The VAS and NDI pain scores reduced and SF-36 scores increased in a 15 or 30 g black soybean daily group compared with a 3 g black soybean daily group after a 24-week therapy (P < 0.05). The 30 g black soybean daily group was better than the 15 g black soybean daily group in relieving chronic cervical pain of sedentary office workers (p < 0.05). The levels of NMDAR were lower in the 15 or 30 black soybean daily group than those in the 3 g black soybean daily group (P < 0.05). Black soybean can ameliorate chronic cervical pain by down-regulating the levels of NMDAR.

Electro-acupuncture for treatment of knee pain from osteoarthritis and the possible endocrinology changes: a study protocol for a randomized controlled trial.

BACKGROUND: Osteoarthritis of the knee is a major cause of disability among adults. Electro-acupuncture is considered a potentially useful treatment for osteoarthritis. The purpose of this study is to assess the efficacy of electro-acupuncture on pain control, pain perception, plasma cortisol and beta-endorphin levels, patient-perceived quality of life, and pain medication use in patients with chronic knee pain. METHODS/DESIGN: This study is a placebo-controlled, randomized, double-blind, parallel design trial. One hundred sixty out-patients who are more than 50 years old and who have osteoarthritis of the knee will be recruited from the island of Mallorca, Spain. Each participant will be randomly placed into one of two groups: (sham) electro-acupuncture non-insertion technique and real electro-acupuncture. Acupuncture treatments will be the Traditional Chinese Medicine type. The patients will be evaluated after a period of 1 month (with two weekly sessions), 3 months (with one monthly session), 6 months (with one session every 45 days), and 1 year later with follow-up sessions at the end of the study (with one session every 2 months). The primary outcomes will be based on the observed changes from the baseline of the visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for pain measured at 12 weeks after the end of treatment. Also to be included in the study are the possible changes in the secondary efficacy variables from baseline as assessed by the Short Form 36 version 2 health survey (patient-perceived quality of life), patient plasma cortisol and beta-endorphin levels at the different treatment stages, the Goldberg Anxiety and Depression Scale, pain medication use, functional capacity and stiffness (WOMAC subscales), and a VAS. These variables will be assessed at 1 month, 3 months, 6 months, and 1 year after study commencement. DISCUSSION: The findings from this study will help to determine whether electro-acupuncture is effective for chronic knee pain management in older people and whether electro-acupuncture can deliver results for the improvement of pain relief, stiffness, and disability. The study will therefore be a major step toward understanding the roles of the hypothalamic-pituitary-adrenal axis and the endogenous opioid system in the effectiveness of electro-acupuncture for chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02299713 (11 Nov. 2014).

Relationship between blood- and cerebrospinal fluid-bound neurotransmitter concentrations and conditioned pain modulation in pain-free and chronic pain subjects.

UNLABELLED: Descending pain inhibition is an endogenous pain control system thought to depend partially on the activation of bulbospinal monoaminergic pathways. Deficits in descending pain inhibition have been reported in numerous human chronic pain conditions, but there is currently no consensus regarding the neurochemical correlates responsible for this deficit. The aims of this study were to 1) assess the efficacy of descending pain inhibition in pain-free and chronic pain subjects, 2) screen for changes in centrally (ie, cerebrospinal fluid) and peripherally (ie, plasma) acting monoamine concentrations, and 3) explore the relationship between descending pain inhibition and monoamine neurotransmitter concentrations. Our results clearly show a deficit in pain inhibition, along with lower plasma norepinephrine and metanephrine concentrations in chronic pain subjects, compared to pain-free subjects. No differences were found in cerebrospinal fluid neurotransmitter concentrations. Finally, our results revealed a positive relationship between blood-bound norepinephrine and metanephrine concentrations and the efficacy of descending pain inhibition. Thus, basal monoamine levels in blood were related to descending pain inhibition. This finding supports the emerging idea that individual differences in descending pain inhibition may be linked to individual differences in peripheral processes, such as monoamines release in blood, which are possibly related to cardiovascular control. PERSPECTIVES: This article presents psychophysical and neurochemical findings that indicate that the latent potential of descending pain inhibitory responses is associated with differential activity in peripheral processes governed by monoamine neurotransmitter release, bringing insights into the relationship between descending pain inhibition and cardiovascular control in humans.

[THE APPLICATION OF ANTIHOMOTOXIC DRUG PREPARATIONS IN THE COMPLEX TREATMENT IN PATIENTS WITH NEUROLOGICAL MANIFESTATIONS OF LUMBAR OSTEOCHONDROSIS].

The expediency of application homeosyniatry by preparations of Traumel S and Placenta Compositum after the offered chart in relation to a complex with classic acupuncture and in relation to the group of the generally accepted treatment has been proved in complex treatment patients with reflex syndromes of lumbar osteochondrosis. A similar conclusion was done after the statistically reliable (P < 0.05) dynamics of parameters of endogenous intoxication, liperoxydation and antioxydant systems of the protection (by the level of katalase, superoxyddismutase, SH-groups, ceruloplasmine).

Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools.

BACKGROUND: Dietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations. OBJECTIVE: To evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. DESIGN: Secondary analysis of a randomized trial. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. RESULTS: Compared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3-L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations. CONCLUSION: Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA.

Crocin improved locomotor function and mechanical behavior in the rat model of contused spinal cord injury through decreasing calcitonin gene related peptide (CGRP).

Various approaches have been offered to alleviate chronic pain resulting from spinal cord injuries (SCIs). Application of herbs and natural products, with potentially lower adverse effects, to cure diseases has been recommended in both traditional and modern medicines. Here, the effect of crocin on chronic pain induced by spinal cord contusion was investigated in an animal model. Female Wistar rats were randomly divided into five groups (5 rats in each); three groups were contused at the L1 level. One group was treated with crocin (150mg/kg) two weeks after spinal cord injury; the second group, control, was treated with vehicle only; and the third group was treated with ketoprofen. Two normal groups were also considered with or without crocin treatment. The mechanical behavioral test, the locomotor recovery test and the thermal behavioral test were applied weekly to evaluate the injury and recovery of rats. Significant improvements (p<0.05) in mechanical behavioral and locomotor recovery tests were seen in the rats treated with crocin. Thermal behavioral test did not show any significant changes due to crocin treatment. Plasma concentration of calcitonin-gene related peptide (CGRP) changed from 780.2±2.3 to 1140.3±4.5pg/ml due to SCI and reached 789.1±2.7pg/ml after crocin treatment. These changes were significant at the level of p<0.05. The present study shows the beneficial effects of crocin treatment on chronic pain induced by SCI, through decreasing CGRP as an important mediator of inflammation and pain.