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      Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study

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          Fibromyalgia is characterized by widespread and chronic pain, and its prevalence is increasing worldwide. Milnacipran, an antidepressant, is often prescribed for fibromyalgia with a possible beneficial effect on central pain modulation. The aim of this study was to evaluate if milnacipran could modify the status of conditioned pain modulation (CPM) in patients suffering from fibromyalgia.

          Design and setting

          Randomized, double-blind controlled trial.

          Subjects and methods

          Women with fibromyalgia received milnacipran 100 mg or placebo. The primary end point was the evolution of CPM with treatments after a 30-second painful stimulus. Secondary outcomes included the predictability of milnacipran efficacy from CPM performance, evolution of global pain, mechanical sensitivity, thermal pain threshold, mechanical allodynia, cognitive function, and tolerance.


          Fifty-four women with fibromyalgia (46.7±10.6 years) were included and randomized, and 24 patients were analyzed in each group. At inclusion, CPM was dysfunctional (CPM 30=−0.5±1.9), and global pain was 6.5±1.8. After treatment, there was a nonsignificant CPM difference between milnacipran and placebo (CPM 30=−0.46±1.22 vs −0.69±1.43, respectively, p=0.55) and 18.8% vs 6.3% ( p=0.085) patients did reactivate CPM after milnacipran vs placebo. Initial CPM was not a predictor of milnacipran efficacy. Global pain, mechanical and thermal thresholds, allodynia, cognition, and tolerance were not significantly different between both groups.


          Milnacipran did not display a significant analgesic effect after 1-month treatment, but the tendency of milnacipran to reactivate CPM in a number of patients must be explored with longer treatment duration in future studies and pleads for possible subtypes of fibromyalgia patients.

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          Most cited references 56

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          Descending control of pain.

           Mark J Millan (2002)
          Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
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            Statistics notes: Analysing controlled trials with baseline and follow up measurements.

             A J Vickers,  D Altman (2001)
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              EULAR evidence-based recommendations for the management of fibromyalgia syndrome.

              To develop evidence-based recommendations for the management of fibromyalgia syndrome. A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords "fibromyalgia", "treatment or management" and "trial". Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and "other pharmacological" and exercise, cognitive behavioural therapy, education, dietary interventions and "other non-pharmacological". In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                10 August 2018
                : 12
                : 2485-2496
                [1 ]University Clermont Auvergne Neurodol, Clermont-Ferrand, France, gisele.pickering@ 123456uca.fr
                [2 ]Clinical Pharmacology Department CPC/CIC Inserm 1405, University Hospital, Clermont-Ferrand, France, gisele.pickering@ 123456uca.fr
                [3 ]Pain Clinic, CHU Clermont-Ferrand, Clermont-Ferrand, France
                [4 ]University Clermont Auvergne MEDIS, CHU Clermont-Ferrand, Clermont-Ferrand, France
                [5 ]DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France
                Author notes
                Correspondence: Gisèle Pickering, Centre de Pharmacologie Clinique, Bâtiment 3C, CIC Inserm 1405, CHU Clermont-Ferrand, BP 69, Clermont-Ferrand Cedex 1 F-63003, France, Tel +33 47 317 8416, Fax +33 47 317 8412, Email gisele.pickering@ 123456uca.fr
                © 2018 Pickering et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine

                fibromyalgia, cpm, milnacipran, antidepressants, pain


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