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1.
Pediatric Erythromelalgia and SCN9A Mutations: Systematic Review and Single-Center Case Series.
Arthur, L, Keen, K, Verriotis, M, Peters, J, Kelly, A, Howard, RF, Dib-Hajj, SD, Waxman, SG, Walker, SM
The Journal of pediatrics. 2019;:217-224.e9
Abstract
OBJECTIVES To evaluate the clinical features of erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Nav1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic erythromelalgia, with or without SCN9A mutations. STUDY DESIGN PubMed, Embase, and PsycINFO Databases were searched for reports of inherited erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing. RESULTS Twenty-eight publications described erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia. CONCLUSIONS Inherited erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need.
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2.
Current understanding of the mixed pain concept: a brief narrative review.
Freynhagen, R, Parada, HA, Calderon-Ospina, CA, Chen, J, Rakhmawati Emril, D, Fernández-Villacorta, FJ, Franco, H, Ho, KY, Lara-Solares, A, Li, CC, et al
Current medical research and opinion. 2019;(6):1011-1018
Abstract
Despite having been referenced in the literature for over a decade, the term "mixed pain" has never been formally defined. The strict binary classification of pain as being either purely neuropathic or nociceptive once left a good proportion of patients unclassified; even the recent adoption of "nociplastic pain" in the IASP Terminology leaves out patients who present clinically with a substantial overlap of nociceptive and neuropathic symptoms. For these patients, the term "mixed pain" is increasingly recognized and accepted by clinicians. Thus, an independent group of international multidisciplinary clinicians convened a series of informal discussions to consolidate knowledge and articulate all that is known (or, more accurately, thought to be known) and all that is not known about mixed pain. To inform the group's discussions, a Medline search for the Medical Subject Heading "mixed pain" was performed via PubMed. The search strategy encompassed clinical trial articles and reviews from January 1990 to the present. Clinically relevant articles were selected and reviewed. This paper summarizes the group's consensus on several key aspects of the mixed pain concept, to serve as a foundation for future attempts at generating a mechanistic and/or clinical definition of mixed pain. A definition would have important implications for the development of recommendations or guidelines for diagnosis and treatment of mixed pain.
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3.
Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers.
Rothenberg, ME, Tagen, M, Chang, JH, Boyce-Rustay, J, Friesenhahn, M, Hackos, DH, Hains, A, Sutherlin, D, Ward, M, Cho, W
Clinical drug investigation. 2019;(9):873-887
Abstract
BACKGROUND AND OBJECTIVE Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that NaV1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel NaV1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects. METHODS This phase I, randomized, double-blind, placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined. RESULTS Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred. CONCLUSION GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.
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4.
Pain and bone damage in rheumatoid arthritis: role of leukotriene B4.
Zheng, LX, Li, KX, Hong, FF, Yang, SL
Clinical and experimental rheumatology. 2019;(5):872-878
Abstract
Rheumatoid arthritis is a chronic autoimmune disease characterised by unbearable joint pain as well as bone and cartilage destruction. Although RA development is greatly controlled, the pain and bone damage failed to be relieved and managed. Leukotriene B4 (LTB4) has been proved to play an essential role in the induction of pain and bone damage. The nerve injury of RA can promote the production of LTB4, which act on their receptors, leading to the increased release of pro-inflammatory cytokines and ROS to reduce neuron viability and pain threshold. Moreover, LTB4-BLT1 activation can also increase intracellular calcium concentration and neuron excitability as well as NF-κB pathway activation, which further promote the production of MMP-9 and CXC3R-1. The mutual promotion between LTB4 and neutrophil accumulation accelerates the release of TNF-α and IL-β, which enhance both peripheral and central nerve system sensitisation. LTB4 also involve in TrpV1 channel activation and modulation of P2X3 receptor activation. All above mechanisms contribute to the development of RA pain. IL-23, cPLA2 and PI3K increase the production of CD11b+Gr1high myeloid subtype and calcium concentration, which promote the production of LTB4 and further accelerate IL-17 and TNF activation as well as calcium influx to conduce to osteoclastogenesis, resulting in aggregated bone damage. Our review is the first to conclude the signalling pathways and associated molecules in LTB4-induced pain and bone damage.
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5.
Phonopheresis Associated with Nanoparticle Gel from Phyllanthus amarus Relieves Pain by Reducing Oxidative Stress and Proinflammatory Markers in Adults with Knee Osteoarthritis.
Decha, P, Kanokwan, K, Jiraporn, T, Pichaya, J, Pisittawoot, A
Chinese journal of integrative medicine. 2019;(9):691-695
Abstract
OBJECTIVE To determine the changes in serum levels of inflammatory biomarkers and antioxidant levels among the knee osteoarthritis (OA) patients after treatment with Phyllanthus amarus (PP) by nanoparticle gel phonophoresis. METHODS This study was a randomized, double-blind, placebo-control, parallel-group, clinical trial involving 30 subjects with mild-to-moderate degree of knee OA. The patients were allocated to two groups using a computer-generated random numbers, and received conventional ultrasound therapy (control group, 15 cases) and PP (treatment group, 15 cases) once daily for 10 sessions. The pain was evaluated by visual analogue scale (VAS). Serum levels of tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbnent assay (ELISA). Nitric oxide (NO) was determined by modified Griess reagent. The antioxidant effects, including superoxide dismutase (SOD) and total antioxidant capacity (TAC), were also measured by ELISA assay. RESULTS The VAS score was significantly decreased in the treatment group compared with the control group after treatment (P<0.01). The serum concentrations of TNF-α and NO were significantly reduced in the treatment group compared with the control group (P<0.01) after treatment. However, the serum concentrations of SOD and TAC in the treatment group were significantly higher after treatment compared with the control group (P<0.01). CONCLUSION PP could alleviate knee pain and significantly reduce systemic anti-inflammatory effects in knee OA patients.
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6.
Gadolinium use for interventional pain procedures: where we are and where we are heading.
Durbhakula, S, Cohen, SP
Regional anesthesia and pain medicine. 2019;(1):4-6
Abstract
In recent years as the use of interventional pain procedures has soared, so too has outside and internal scrutiny. This scrutiny includes agreater emphasis on weighing the risks and benefits of procedures, increased surveillance for adverse events, and cost containment strategies. In 2016, the first reports of gadolinium deposition in the central nervous system began to surface, though retention in other organ systems has been appreciated for over a decade. In this issue of Regional Anesthesia & Pain Medicine, Benzon et al. report a series of patients with document edhypersensitivity reactions to iodinated contrast medium who were inadvertently administered iodine-based contrast without adverse consequences. In this article, we discuss the epidemiology of contrast-mediated adverse effects, the mechanistic basis for hypersensitivity reactions, the risks and benefits of various approaches in the patient with a documented contrast hypersensitivity reaction, and risk mitigation strategies.
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7.
Pain catastrophizing: rumination is a discriminating factor among individuals with different pain characteristic.
Bonafé, FSS, Campos, LA, Marôco, J, Campos, JADB
Brazilian oral research. 2019;:e113
Abstract
The objective of this study was to compare the scores of the Helplessness, Magnification, Rumination, and Catastrophizing factors of the Pain Catastrophizing Scale (PCS) between samples with different pain characteristics. The psychometric properties of the PCS were evaluated in 1,151 Brazilian adults (78.9% female; 38.6 (SD = 10.8) years): 335 had no pain, 390 had been in pain for less than 3 months, 250 had been in recurring pain for more than 3 months, and 176 had been in continuous pain for more than 3 months. Confirmatory factor analysis (CFA) was conducted to verify the fit of the PCS models. Convergent validity and reliability were evaluated. Multi-group analysis was used to estimate the invariance of the factorial model. The global score for the PCS factors was obtained using the regression weight matrix for estimating factor scores from CFA. Analysis of variance was used to compare scores between samples. After excluding three items, the tri-factorial model showed adequate fit. The model parameters were invariant (Δχ2(λ,i,β,Res); p≥0.05). Individuals experiencing pain showed higher scores for catastrophic thoughts. Individuals with pain for less than 3 months had the highest scores for Rumination (p < 0.001). The PCS showed valid, reliable, and invariant results for the sample of Brazilian adults in no pain or with different pain conditions. The PCS adequately discriminated individuals in pain from those without pain. Among those in pain, Rumination was the only discriminating factor.
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8.
Management of pain in individuals with spinal cord injury: Guideline of the German-Speaking Medical Society for Spinal Cord Injury.
Franz, S, Schulz, B, Wang, H, Gottschalk, S, Grüter, F, Friedrich, J, Glaesener, JJ, Bock, F, Schott, C, Müller, R, et al
German medical science : GMS e-journal. 2019;:Doc05
Abstract
Introduction: Pain is a prominent complication in spinal cord injury (SCI). It can either occur as a direct or as an indirect consequence of SCI and it often heavily influences the quality of life of affected individuals. In SCI, nociceptive and neuropathic pain can equally emerge at the same time above or below the level of injury. Thus, classification and grading of pain is frequently difficult. Effective treatment of SCI-related pain in general and of neuropathic pain in particular is challenging. Current treatment options are sparse and their evidence is considered to be limited. Considering these aspects, a clinical practice guideline was developed as basis for an optimized, comprehensive and standardized pain management in SCI-related pain. Methods: The German-Speaking Medical Society for Spinal Cord Injury (Deutschsprachige Medizinische Gesellschaft für Paraplegiologie - DMGP) developed a clinical practice guideline that received consensus from seven further German-speaking medical societies and one patient organization. The evidence base from clinical trials and meta-analyses was summarized and subjected to a structured consensus-process in accordance with the regulations of the Association of Scientific Medical Societies in Germany (AWMF) and the methodological requirements of the "German instrument for methodological guideline appraisal". Results: This consensus-based guideline (S2k classification according to the AWMF guidance manual and rules) resulted in seven on-topic statements and 17 specific recommendations relevant to the classification, assessment and therapy of pain directly or indirectly caused by SCI. Recommended therapeutic approaches comprise pharmacological (e.g. nonsteroidal anti-inflammatory drugs or anticonvulsants) and non-pharmacological (e.g. physical activity or psychotherapeutic techniques) strategies for both nociceptive and neuropathic pain. Discussion: Assessment of SCI-related pain is standardized and respective methods in terms of examination, classification and grading of pain are already in use and validated in German language. In contrast, valid, evidence-based and efficient therapeutic options are limited and ask for further clinical studies, ideally randomized controlled trials and meta-analyses.
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9.
P2X receptors and trigeminal neuralgia.
Li, JJ, Liu, ZX, Zhang, YL, Xue, GY
Neuroreport. 2019;(10):725-729
Abstract
There is currently no effective cure for trigeminal neuralgia (TN) - a relatively common disease that causes long-term pain in patients. Previous research has shown that ionotropic ATP signaling through excitatory and calcium-permeable P2X receptor channels plays a critical role in pathological pain generation and maintenance. In this paper, we review several hypotheses on the pathogenic mechanisms underlying TN. We further discuss pathways or agents that can target P2X expression in TN, thereby affecting pain induction and maintenance.
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10.
Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain.
Barra, F, Scala, C, Ferrero, S
Drugs of today (Barcelona, Spain : 1998). 2019;(4):237-246
Abstract
First-line medical therapies for treating pain associated with endometriosis mainly consist in combined oral contraceptives and progestins. However, some women, having persistence of symptoms, may require further therapeutic options. Among these, gonadotropin-releasing hormone (GnRH) agonists (GnRH-as) have been widely employed in the last 30 years, despite being characterized by an unfavorable safety profile. Currently, new alternative investigational options are being investigated to treat this benign chronic disease. GnRH antagonists (GnRH-ants) are innovative hormonal drugs that do not induce flare-up effects and present also a limited onset of hypoestrogenic symptoms; in fact, their pharmacological mechanism of action, which consists in pure antagonistic activity, differs from that of traditional GnRH-as. In July 2018, the U.S. Food and Drug Administration (FDA) approved elagolix sodium for the management of moderate to severe pain associated with endometriosis, after the drug showed promising efficacy and safety results in previous phase III trials. This monograph aims to provide a complete overview of the pharmacokinetics, clinical efficacy and safety of this GnRH-ant for treat¬ing patients with endometriosis.