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Polygenic risk scores indicates genetic overlap between peripheral pain syndromes and chronic postsurgical pain.
van Reij, RRI, Voncken, JW, Joosten, EAJ, van den Hoogen, NJ
Neurogenetics. 2020;(3):205-215
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Abstract
Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that has a substantial effect on quality of life. CPSP shows considerable clinical overlap with different chronic peripheral pain syndromes, suggesting a shared aetiology. This study aims to assess the genetic overlap between different chronic pain syndromes and CPSP, providing relevant biological context for potential chronic pain markers of CPSP. To analyse the genetic overlap between CPSP and chronic peripheral pain syndromes, recent GWAS studies were combined for polygenic risk scores (PRS) analysis, using a cohort of CPSP patients as starting point. Biological contextualisation of genetic marker, overlap between CPSP and chronic pain syndromes, was assessed through Gene Ontology (GO), using Pathway Scoring Algorithm (PASCAL) and REVIGO. PRS analyses suggest a significant genetic overlap between CPSP and 3 chronic pain disorders: chronic widespread pain (CWP, p value threshold = 0.003, R2 0.06, p = 0.003), rheumatoid arthritis (RA, p value threshold = 0.0177, R2 = 0.04, p = 0.017) and possibly sciatica (p value threshold = 0.00025, R2 = 0.03, p = 0.045). Whereas no significant genetic overlap was found with cluster headache and migraine, the outcome for osteoarthritis (OA) was inconsistent between the cohorts. This is likely related to cohort composition, as repeated random reallocation of patients' nullified CPSP/OA outcome variation between the discovery and replication cohorts. GO analyses suggested an aetiological involvement of genetic markers that control neurological signalling (specifically sodium channels) and inflammatory response. The current study reaffirms the impact of sample size, cohort composition and open data accessibility on the unbiased identification of genetic overlap across disorders. In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory response may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate.
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A Rosa canina - Urtica dioica - Harpagophytum procumbens/zeyheri Combination Significantly Reduces Gonarthritis Symptoms in a Randomized, Placebo-Controlled Double-Blind Study.
Moré, M, Gruenwald, J, Pohl, U, Uebelhack, R
Planta medica. 2017;(18):1384-1391
Abstract
The special formulation MA212 (Rosaxan) is composed of rosehip (Rosa canina L.) puree/juice concentrate, nettle (Urtica dioica L.) leaf extract, and devil's claw (Harpagophytum procumbens DC. ex Meisn. or Harpagophytum zeyheri Decne.) root extract and also supplies vitamin D. It is a food for special medical purposes ([EU] No 609/2013) for the dietary management of pain in patients with gonarthritis.This 12-week randomized, placebo-controlled double-blind parallel-design study aimed to investigate the efficacy and safety of MA212 versus placebo in patients with gonarthritis.A 3D-HPLC-fingerprint (3-dimensional high pressure liquid chromatography fingerprint) of MA212 demonstrated the presence of its herbal ingredients. Ninety-two randomized patients consumed 40 mL of MA212 (n = 46) or placebo (n = 44) daily. The Western Ontario and McMaster Universities Arthritis Index (WOMAC), quality-of-life scores at 0, 6, and 12 weeks, and analgesic consumption were documented. Statistically, the initial WOMAC subscores/scores did not differ between groups. During the study, their means significantly improved in both groups. The mean pre-post change of the WOMAC pain score (primary endpoint) was 29.87 in the MA212 group and 10.23 in the placebo group. The group difference demonstrated a significant superiority in favor of MA212 (pU < 0.001; pt < 0.001). Group comparisons of all WOMAC subscores/scores at 6 and 12 weeks reached same significances. Compared to placebo, both physical and mental quality of life significantly improved with MA212. There was a trend towards reduced analgesics consumption with MA212, compared to placebo. In the final efficacy evaluation, physicians (pChi < 0.001) and patients (pChi < 0.001) rated MA212 superior to placebo. MA212 was well tolerated.This study demonstrates excellent efficacy for MA212 in gonarthritis patients.
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Unsaponifiable Fraction of Unripe Fruits of Olea europaea: An Interesting Source of Anti-inflammatory Constituents.
Gelmini, F, Ruscica, M, Macchi, C, Bianchi, V, Maffei Facino, R, Beretta, G, Magni, P
Planta medica. 2016;(3):273-8
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Abstract
The unsaponifiable fraction of olive oil from unripe fruits of Olea europaea at different stages of maturation (from 20 to 32 weeks after flowering) was analyzed by gas chromatography-mass spectrometry in order to select the time associated to the unsaponifiable fraction with the maximal yield in bioactive constituents. According to quantitative gas chromatography-mass spectrometry analysis, the unsaponifiable fraction (2.46% of the total oil) from olive fruits at the 22nd week was found to contain the maximal yield in anti-inflammatory constituents. Its composition was lanosterol (2.60 mg/g oil), stigmasterol (2.15), cycloartanol acetate (2.04), stigmastan-3,5-diene (2.01), obtusifoliol (1.93), cholesta-4,6-dien-3-one (1.42), α-amyrin (1.42), α-tocopherol (1.32), squalene (1.02), β-amyrin (0.57), and β-sitosterol (0.22). At later times, there was a decrease in the quantitative unsaponifiable fraction yield and a qualitative shift in the bioactive constituents. The 22nd week unsaponifiable fraction was subsequently incorporated into a topical preparation to be utilized for a small pilot clinical study in five patients affected by osteoarthrosis. According to clinical observation, the application of the ointment (three times daily for three weeks) attenuated hand and knee joint inflammatory features in all patients and was not associated to any adverse reactions.
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[The external application of "Plastunskaya" fluoride-containing mineral water in the course of the combined spa and health resort-based treatment of deforming osteoarthrosis].
Mel'nichuk, LP, Khodasevich, LS
Voprosy kurortologii, fizioterapii, i lechebnoi fizicheskoi kultury. 2015;(6):48-50
Abstract
Mineral waters containing fluorine (fluorinated waters) at a concentration in excess of 1 mg per liter are extensively used in the newly developing spa and health resort areas of the Russian Federation. They have been found in Siberia, Trans-Baikal regions, and the Krasnodar Territory (together with the Greater Sochi). These waters are mainly used for drinking as a component of the balneo- therapeutic treatment. In this context, the study of the therapeutic effects of low-mineralized hydrocarbonate-sodium waters containing fluorine in high concentrations is of paramount importance for the substantiation and facilitation of their external application in the framework of the programs of combined spa and health resort-based treatment of various diseases. We have investigated the possibility of the external application of "Plastunskaya" mineral water characterized above all by the high content of fluorine for the external treatment of osteoarthritis in 187 patients at the age varying from 37 to 63 years in the combination with the sparing regimen of physical activity, therapeutic physical exercises, klimatotherapy of moderate intensity, and a balanced diet. The patients were prescribed to take general "Plastunskaya" mineral water baths with the fluoride concentration of 7.4 mg/l at a temperature of 36 C from 7 to 15 minutes in duration for 2 consecutive days with a break on every third day (the total course consisted of 14-16 baths). It was shown that the combined treatment with the use of fluorine-containing mineral water resulted in the significant improvement of the clinical and biochemical parameters characterizing the health status of the patients suffering from deforming osteoarthrosis.
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Impact of concomitant low-dose aspirin on the safety and tolerability of naproxen and esomeprazole magnesium delayed-release tablets in patients requiring chronic nonsteroidal anti-inflammatory drug therapy: an analysis from 5 Phase III studies.
Angiolillo, DJ, Datto, C, Raines, S, Yeomans, ND
Journal of thrombosis and thrombolysis. 2014;(1):11-23
Abstract
Patients receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) and concomitant low-dose aspirin (LDA) are at increased risk of gastrointestinal (GI) toxicity. A fixed-dose combination of enteric-coated (EC) naproxen and immediate-release esomeprazole magnesium (NAP/ESO) has been designed to deliver a proton-pump inhibitor followed by an NSAID in a single tablet. To examine safety data from 5 Phase III studies of NAP/ESO in LDA users (≤ 325 mg daily, administered at any time during the study), and LDA non-users, data were analyzed from 6-month studies assessing NAP/ESO versus EC naproxen in patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis (n = 2), 3-month studies assessing NAP/ESO vs celecoxib or placebo in patients with knee osteoarthritis (n = 2), and a 12-month, open-label, safety study of NAP/ESO (n = 1). In an analysis of two studies, incidences of endoscopically confirmed gastric ulcers (GUs) and duodenal ulcers (DUs) were summarized by LDA subgroups. In the pooled analysis from all five studies, incidences of treatment-emergent adverse events (AEs) (including prespecified NSAID-associated upper GI AEs and cardiovascular AEs), serious AEs, and AE-related discontinuations were stratified by LDA subgroups. Overall, 2,317 patients received treatment; 1,157 patients received NAP/ESO and, of these, 298 received LDA. The cumulative incidence of GUs and DUs in the two studies with 6-month follow-up was lower for NAP/ESO vs EC naproxen in both LDA subgroups [GUs: 3.0 vs 27.9%, respectively, for LDA users, 6.4 vs 22.4%, respectively, for LDA non-users (both P < 0.001); DUs: 1.0 vs 5.8% for LDA users, 0.6 vs 5.3% for LDA non-users]. The incidence of erosive gastritis was lower in NAP/ESO- vs EC naproxen-treated patients for both LDA users [18.2 vs 36.5%, respectively (P = 0.004)] and LDA non-users [19.8 vs 38.5%, respectively (P < 0.001)]. Among LDA users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 16.1%; EC naproxen, 31.7%; celecoxib, 22.1%; placebo, 23.2%. Among LDA non-users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 20. %; EC naproxen, 36.6%; celecoxib, 18.5%; placebo, 18.9%. For LDA users, incidences of cardiovascular AEs were: NAP/ESO, 3.0%; EC naproxen, 1.0%; celecoxib, 0%; placebo, 0%. For LDA non-users, incidences of cardiovascular AEs were: NAP/ESO, 1.0%; EC naproxen, 0.6%; celecoxib, 0.3%; placebo, 0%. NAP/ESO appears to be well-tolerated in patients receiving concomitant LDA. For LDA users, AE incidence was less than that observed for EC naproxen. For most AE categories, incidences were similar among NAP/ESO, celecoxib and placebo groups. The safety of NAP/ESO appeared similar regardless of LDA use.
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A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain.
Conrozier, T, Mathieu, P, Bonjean, M, Marc, JF, Renevier, JL, Balblanc, JC
Alternative therapies in health and medicine. 2014;:32-7
Abstract
BACKGROUND Devil's claw (Harpagophytum procumbens), turmeric (Curcuma longa), and bromelain are nutraceuticals that have demonstrated anti-inflammatory and analgesic properties and may be potential solutions in the treatment of acute or chronic joint pain. Their analgesic effect, however, is generally considered mild to moderate, and the relevance of their clinical use remains subject to discussion. OBJECTIVES The aim of the study was to evaluate the clinical relevance of the efficacy of a marketed complex of 3 plant extracts-H procumbens, C longa, and bromelain (AINAT, 650 mg)-in the treatment of degenerative joint pain. METHODS A multicenter, observational, prospective, open-label survey was conducted in 8 rheumatology centers. The study included 2 groups, 1 group with participants suffering from chronic osteoarthritis (OA) pain and 1 group suffering from acute OA pain. SETTING The research team carried out the study under daily practice conditions. PARTICIPANTS A total of 42 patients (36 women; mean age = 67 y) suffering from acute or chronic, degenerative spine or joint pain participated. INTERVENTION Two 650-mg capsules of AINAT were administered 3 ×/d to patients with acute pain and 2 ×/d to patients with chronic pain. OUTCOME MEASURES At baseline, and during a follow-up visit at 15 d for the acute pain group and 60 d for the chronic pain group, the research team obtained each participant's global assessment (PGA) and each rheumatologist's global assessment (RGA), as well as each participant's pain score, using for each of them a 100-mm visual analogue scale (VAS). The clinical relevance of the efficacy was evaluated by comparing the outcome measures at endpoint to the values defining the patient acceptable symptom state (PASS) and by comparing the variations (in mm and %) between baseline and endpoint to those defining the minimal clinically important improvement (MCII). Tolerance was also assessed by collecting adverse events at each visit and by using a 4-point scale (very good to bad) at the endpoint. RESULTS At baseline, the VAS pain score (standard deviation) was 69.1 mm (15.4) and 68.0 mm (18.2) for patients with acute and chronic pain, respectively. At the endpoint, the scores decreased to 42.1 mm (21.1) and 37.8 mm (25.9), respectively. This reduction of pain, as a percentage as well as an absolute value, corresponds to the required definition of MCII, particularly in patients with chronic joint pain. At the endpoint, most of the patients in both groups reached the level of pain defined as the PASS. No withdrawals occurred due to treatment side effects. CONCLUSION The improvement of joint pain was clinically relevant in patients treated with AINAT for both acute and chronic OA pain. Considering its excellent tolerance profile, the tested complex of 3 plant extracts with antiinflammatory properties may be a valuable and safe alternative to NSAIDs in patients suffering from degenerative joint diseases.
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Willow bark extract STW 33-I in the long-term treatment of outpatients with rheumatic pain mainly osteoarthritis or back pain.
Uehleke, B, Müller, J, Stange, R, Kelber, O, Melzer, J
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2013;(11):980-4
Abstract
STUDY OBJECTIVE Efficacy and safety of willow bark extract for pain reduction in patients suffering from musculoskeletal disorders (MSD) has been shown in clinical short term trials. Therefore this observational study over 6 months should evaluate patterns of treatments like mono- or combinations therapy, dosage and safety during long-term treatment under pragmatic conditions with the aqueous willow bark extract STW 33-I, (Proaktiv(®); drug-extract-ratio 16-23:1). PATIENTS AND METHODS The patients were treated with STW 33-I; comedication with other NSAIDs and opioids was allowed. An extensive case report form including pain questionnaires and patient diary was used for outcome evaluation. RESULTS Four hundred and thirty-six patients with rheumatic pain mainly due to osteoarthritis (56.2%) and back pain (59.9%) were included. During the study the mean reductions from baseline value 58.4±22.6-31.8±22.5 after 24 weeks in the pain intensity scale (VAS 0-100mm) were significant even after 3 weeks with a reduction by 26 mm (45.6% of the baseline value) at the end of the study. The relative reductions of the weekly means of the daily patient self-rated scores of the pain (6-point Likert-scales) were between 33% and 44% of the baseline values during the course of the study. We present results of subgroups according their analgetic/antiphlogistic comedication. The distribution and specification of the main adverse events and the ratings of the treatment showed a good tolerability. No relevant drug interactions were reported. CONCLUSION These data suggest that STW 33-I can be used as a basic treatment in the long-term therapy of painful musculoskeletal disorders and that it can be combined with NSAIDs and opioids if necessary.
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Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: phase III study in patients at risk for NSAID-associated gastric ulcers.
Sostek, MB, Fort, JG, Estborn, L, Vikman, K
Current medical research and opinion. 2011;(4):847-54
Abstract
OBJECTIVE To evaluate long-term safety of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg fixed-dose combination (FDC) in patients at risk of NSAID-associated upper gastrointestinal (UGI) ulcers. RESEARCH DESIGN AND METHODS In this open-label, multicenter, phase III study, Helicobacter pylori-negative patients aged ≥50 years or 18-49 years with history of uncomplicated ulcer within the past 5 years, who had osteoarthritis, rheumatoid arthritis, or other condition requiring daily NSAIDs for ≥12 months received naproxen/esomeprazole twice daily for 12 months. CLINICAL TRIAL REGISTRATION NCT00527904. MAIN OUTCOME MEASURES Adverse events (AEs), vital signs, physical examination, and laboratory tests. Subgroup analyses included age and low-dose aspirin (LDA) use. Predefined NSAID-associated UGI and cardiovascular AEs were analyzed. RESULTS Of 239 patients treated (safety population), 135 completed ≥348 treatment days (12-month completers). AE incidence was approximately 70%; dyspepsia, constipation, upper respiratory tract infection, nausea, back pain, and contusion were most frequent (≥5% patients, either population). Treatment-related AEs occurred in 28.0% and 23.7% of patients in the safety and 12-month completer populations, respectively; 18.8% of patients withdrew due to AEs (safety population). Few serious AEs and no deaths occurred. In the safety population, AE incidence was 71.4% and 76.9% in patients aged <65 years (n = 161) and ≥65 years (n = 78), respectively, and 67.6% and 75.8% in LDA users (n = 74) and non-users (n = 165), respectively. Predefined UGI and cardiovascular AEs were observed in 18.8% and 6.3% of patients, respectively, in the safety population, and 16.3% and 5.2%, respectively, in 12-month completers. Dyspepsia and hypertension were most common. Additional assessments showed no unexpected findings. CONCLUSIONS Based on these outcome measures, long-term treatment with FDC naproxen/esomeprazole is not associated with any new safety issues, including predefined UGI and cardiovascular AEs, in patients requiring NSAID therapy who are at risk of UGI complications.
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A prospective observational study of the clinical efficacy and safety of intra-articular sodium hyaluronate in synovial joints with osteoarthritis.
Foti, C, Cisari, C, Carda, S, Giordan, N, Rocco, A, Frizziero, A, Della Bella, G
European journal of physical and rehabilitation medicine. 2011;(3):407-15
Abstract
BACKGROUND Clinical trials have demonstrated the safety and efficacy of hyaluronic acid-based products for the treatment of synovial joints affected by osteoarthritis (OA), but data from observational studies of normal medical practice are sparse. AIM: This study investigated the safety and efficacy of intra-articular (IA) sodium hyaluronate (MW 1500-2000 KDa; Hyalubrix®) in the treatment of synovial joint OA. DESIGN This is prospective, and observational study. SETTING This study was carried out at 47 specialist centers for physiatrists, orthopedics and rheumatology in Italy; the enrolled population, 1266 outpatient, was predominantly female (66%, 840/1266), with a mean age of 66 years, and a mean weight of 74 kg. POPULATION The Participants with OA received IA injections of the study treatment (2 mL) once per week for 3 weeks. The knee was the joint most commonly affected by OA (right knee 802/1266 [63%]; left knee 598/1266 [47%]), and the longest median duration of disease occurred in the carpal joint (right carpal joint 40 months; left carpal joint 60 months). METHODS The primary endpoints were tolerability and details of usage of the IA sodium hyaluronate syringe device. Efficacy parameters included assessment of self-reported pain via the Visual Analogue Scale (VAS), and evaluation of motor function via the Health Assessment Questionnaire (HAQ). Quality of life (QoL) was assessed using the Euro QoL questionnaire (Clinical Trial Registration Number: ISRCTN 42690497). RESULTS Data from 1266 participants were collected. The adverse event (AE) rate was 0.8% (95% CI, 0.4 to 1.5). Thirteen AEs were reported, 12 of which were mild or moderate in severity. Only one participant discontinued study treatment following an AE. No serious adverse events occurred. Coadministration of local anesthetic was required by up to 10% of patients. Statistically significant improvements in VAS, HAQ and EuroQoL were recorded in multiple joints (P<0.0001 for each). CONCLUSION The study treatment was safe and well tolerated. CLINICAL REHABILITATION IMPACT . The study treatment reduced pain, improved mobility, and increased QoL in participants with OA.
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Phellodendron and Citrus extracts benefit joint health in osteoarthritis patients: a pilot, double-blind, placebo-controlled study.
Oben, J, Enonchong, E, Kothari, S, Chambliss, W, Garrison, R, Dolnick, D
Nutrition journal. 2009;:38
Abstract
BACKGROUND The objective of this clinical study was to assess the potential benefit of a dietary supplement, NP 06-1, on joint health in overweight and normal weight adults diagnosed with osteoarthritis. METHODS An 8-week placebo-controlled, randomized, double-blind study was conducted with four groups comparing the effects of NP 06-1 to placebo on overweight and normal weight subjects diagnosed with primary osteoarthritis of the knee. NP 06-1 (a combination of two botanical extracts; Phellodendron amurense bark and Citrus sinensis peel) or matching placebo were given in a dose of two capsules (370 mg each) twice daily. The outcome measures were the Lequesne Algofunctional Index (LAI) for joint pain and movement as well as biomarkers of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]). RESULTS Eighty (80) subjects were enrolled and 45 subjects completed the study. No serious adverse events were reported. The mean total LAI scores at baseline for the four groups ranged from 11.4 to 12.4 (SD 1.2 to 2.4). Treatment for 8 weeks resulted in a statistical improvement in the LAI score in the overweight treatment group compared to placebo (6.3 +/- 2.3 vs 11.8 +/- 1.5; p < 0.0001). At 8 weeks, a similar result was observed in the normal weight groups (7.7 +/- 1.4 vs 9.9 +/- 0.9; p < 0.0001). There was a reduction in CRP levels with treatment in the overweight treatment group at 8 weeks (-0.62 +/- 0.2; 49%) compared to baseline (p < 0.001) and to placebo (p < 0.001). For the normal weight participants, there were significant reductions in CRP compared to baseline, but not to the matched placebo group. Both overweight and normal weight treatment groups lost a significant amount of weight compared to their placebo groups. The overweight treatment group lost an average of 5% body weight after 8 weeks. There was no significant change in ESR in any of the groups. CONCLUSION In this pilot study, NP 06-1 had beneficial effects on symptoms of osteoarthritis of the knee as measured using LAI scores and had anti-inflammatory effects as measured using CRP. Administration of NP 06-1 was also associated with weight loss, which may have been a contributing factor to the other benefits.