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      Randomized controlled trial about pain medication flupirtine ignores recent pharmacovigilance warnings

      1 , 2

      Journal of Pain Research

      Dove Medical Press

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          Abstract

          Dear editor On October 16, 2017 in the Journal of Pain Research, a randomized controlled trial (RCT) comparing efficacy and safety of flupirtine versus piroxicam in postoperative pain in patients undergoing lower limb surgery was published.1 However, this paper fails to report important information. First, the paper describes a study in which flupirtine, a pain medication, was used. Because pharmacovigilance signals potentially severe liver toxicity, in 2013 the European Medicines Agency (EMA) recommended restrictions in the use of flupirtine-containing medications.2 According to those restrictions, flupirtine-containing medications need to be used only for short-term pain when other analgesics are contraindicated, that is, for not more than 14 days; the drug should not be given to people with preexisting liver disease, alcohol abuse, or other hepatotoxic drugs. Liver function should also be monitored after each week of therapy and the treatment should be discontinued if there are any signs of liver problems.2 The recommendation about restricting therapy to 14 days was based on the EMA’s observation that “no cases of liver failure or liver transplantation were reported for patients that were taking flupirtine-containing medicines for 2 weeks or less.”2 However, in 2014, Douros et al3 analyzed cases of flupirtine-induced liver injury (FILI) in Germany as well as severe cases of hepatotoxicity from the database of German drug regulator, and concluded that even though the risk of liver toxicity is higher after 14 days, that an even earlier onset of severe FILI cannot be ruled out. Last year, an association between haplotype DRB1*16:01-DQB1*05:02 and FILI was reported.4 Considering all these information about potential severe liver toxicity induced by flupirtine, it is surprising that a new RCT being published does not even mention flupirtine’s potential to induce hepatotoxicity, and that measurements of liver enzymes were also not reported. The only information in the “Introduction” section regarding flupirtine safety is “It is devoid of adverse effects like gastritis, renal compensation, and respiratory depression and therefore found to be safe in most patients.”1 This trial was reportedly conducted from January 2015 to July 2016, when information related to liver toxicity and flupirtine safety were already available. Regulatory warnings about drugs should be utilized to introduce appropriate safety monitoring in clinical trials and to ensure patient safety. Second, the paper describes an RCT conducted on humans and details about the trial registration were not mentioned. Since 2005, International Committee of Medical Journal Editors requires mandatory prospective registration of clinical trials. If there are trials registered, which plan to use medicines that are subject of regulatory warnings, principal investigators can be contacted and could be warned about recent pharmacovigilance signals related to patient safety.

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          Most cited references 8

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          Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study.

          In cell culture experiments, flupirtine maleate (FLU), a triaminopyridine compound, was able to protect neuronal cells from apoptotic cell death induced by prion protein fragments and beta-amyloid peptides. As FLU is a clinically safe drug, the authors started a double-blind placebo-controlled study in patients with Creutzfeldt-Jakob disease (CJD). Twenty-eight patients with CJD were randomized to an oral treatment with either FLU (n = 13) or matching placebo (PLA; n = 15). For inclusion and continuing the study, the patients had to achieve at least 50% in two of the subscales of the dementia tests employed. A battery of standardized questionnaires was employed to monitor the progression of the disease. The main outcome variable was the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-Cog); the difference between baseline and the best score under treatment was defined as the primary efficacy variable for hypothesis testing. CJD types were homogeneously distributed among the treatment groups. Patients treated with FLU showed significantly less deterioration in the dementia tests than patients treated with PLA. The mean change in ADAS-Cog (baseline to best) was +8.4 (+/-15.3) in the FLU group and +20.6 (+/-15.1) in the PLA group (p = 0.02, one-sided t-test). FLU has beneficial effects on cognitive function in patients with CJD. These positive results also may suggest a treatment potential of FLU in other neurodegenerative disorders. However, further studies are necessary.
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            HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury.

            Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown.
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              Flupirtine-induced liver injury--seven cases from the Berlin Case-control Surveillance Study and review of the German spontaneous adverse drug reaction reporting database.

              The hepatotoxic potential of the analgesic flupirtine has attracted increased attention over the past years. Recently, risk minimisation measures such as maximum treatment duration of 2 weeks have been requested by the European Medicines Agency (EMA). This study was conducted to further elucidate the clinical pattern of flupirtine-induced liver injury (FILI).
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2018
                12 January 2018
                : 11
                : 177-180
                Affiliations
                [1 ]Laboratory for Pain Research, University of Split School of Medicine, Split, Croatia
                [2 ]Department for Development, Research and Health Technology Assessment, Agency for Quality and Accreditation in Health Care and Social Welfare, Zagreb, Croatia
                [1 ]Department of Pharmacology
                [2 ]Department of Orthopedics, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Karnataka, India
                Author notes
                Correspondence: Livia Puljak, Laboratory for Pain Research, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia, Tel +385 21 557 807, Fax +385 21 557 811, Email livia@ 123456mefst.hr
                Correspondence: Narayana Sarala, Department of Pharmacology, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar, Karnataka, 563103, India, Tel +91 984 575 0165, Email n_sarala@ 123456rediffmail.com
                Article
                jpr-11-177
                10.2147/JPR.S154447
                5769781
                © 2018 Puljak. 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.

                Categories
                Letter

                Anesthesiology & Pain management

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