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      Towards an Effective and Safe Treatment of Inflammatory Pain: A Delphi-Guided Expert Consensus

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          Abstract

          Objective

          The clinical management of inflammatory pain requires an optimal balance between effective analgesia and associated safety risks. To date, mechanisms associated with inflammatory pain are not completely understood because of their complex nature and the involvement of both peripheral and central mechanisms. This Expert Consensus document is intended to update clinicians about evolving areas of clinical practice and/or available treatment options for the management of patients with inflammatory pain.

          Method

          An international group of experts in pain management covering the pharmacology, neurology and rheumatology fields carried out an independent qualitative systematic literature search using MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials.

          Results

          Existing guidelines for pain management provide recommendations that do not satisfactorily address the complex nature of pain. To achieve optimal outcomes, drug choices should be individualized to guarantee the best match between the characteristics of the patient and the properties of the medication. NSAIDs represent an important prescribing choice in the management of inflammatory pain, and the recent results on paracetamol question its appropriate use in clinical practice, raising the need for re-evaluation of the recommendations in the clinical practice guidelines.

          Conclusions

          Increasing clinicians’ knowledge of the available pharmacologic options to treat different pain mechanisms offers the potential for safe, individualized treatment decisions. We hope that it will help implement the needed changes in the management of inflammatory pain by providing the best strategies and new insights to achieve the ultimate goal of managing the disease and obtaining optimal benefits for patients.

          Funding

          Dompé Farmaceutici SPA and Paolo Procacci Foundation.

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          Most cited references101

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          Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome.

          NLRP3 forms an inflammasome with its adaptor ASC, and its excessive activation can cause inflammatory diseases. However, little is known about the mechanisms that control assembly of the inflammasome complex. Here we show that microtubules mediated assembly of the NLRP3 inflammasome. Inducers of the NLRP3 inflammasome caused aberrant mitochondrial homeostasis to diminish the concentration of the coenzyme NAD(+), which in turn inactivated the NAD(+)-dependent α-tubulin deacetylase sirtuin 2; this resulted in the accumulation of acetylated α-tubulin. Acetylated α-tubulin mediated the dynein-dependent transport of mitochondria and subsequent apposition of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. Therefore, in addition to direct activation of NLRP3, the creation of optimal sites for signal transduction by microtubules is required for activation of the entire NLRP3 inflammasome.
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            Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials.

            Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. Depression scores after treatment and adverse effects. Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.
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              Is Open Access

              Neuroinflammation and psychiatric illness

              Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.
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                Author and article information

                Contributors
                giuvarr@gmail.com
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                16 August 2019
                16 August 2019
                2019
                : 36
                : 10
                : 2618-2637
                Affiliations
                [1 ]Paolo Procacci Foundation, Rome, Italy
                [2 ]President of World Institute of Pain (WIP), Winston-Salem, NC USA
                [3 ]GRID grid.7400.3, ISNI 0000 0004 1937 0650, University of Zurich, ; Zurich, Switzerland
                [4 ]Medical Affairs Department, Dompé Farmaceutici SpA, Milan, Italy
                [5 ]University of Belvitge, Barcellona, Spain
                [6 ]GRID grid.158820.6, ISNI 0000 0004 1757 2611, Department of MESVA, , University of L’Aquila, ; L’Aquila, Italy
                [7 ]GRID grid.459798.e, NEMA Research Inc, ; Naples, FL USA
                [8 ]GRID grid.411394.a, ISNI 0000 0001 2191 1995, Descartes University and Cochin-Hotel Dieu Hospital, ; Paris, France
                [9 ]GRID grid.10383.39, ISNI 0000 0004 1758 0937, University of Parma, ; Parma, Italy
                [10 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, University of Munich, ; Munich, Germany
                Author information
                http://orcid.org/0000-0002-3822-2923
                Article
                1053
                10.1007/s12325-019-01053-x
                6822819
                31485978
                ab10e39e-4714-4133-b7a2-ff8ebbf379da
                © The Author(s) 2019
                History
                : 13 May 2019
                Funding
                Funded by: Dompé Farmaceutici
                Funded by: Paolo Procacci Foundation
                Categories
                Review
                Custom metadata
                © Springer Healthcare Ltd., part of Springer Nature 2019

                adjuvant drugs,inflammation,inflammatory pain,neurogenic pain,neuroinflammation,nsaids,opioids,pain

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