Neuropathic Pain Clinical Trials: Factors Associated with Decreases in Estimated Drug Efficacy

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  • Nanna B Finnerup
  • Simon Haroutounian, Division of Clinical and Translational Research, Department of Anesthesiology, and Pain Center, Washington University in St. Louis School of Medicine, St Louis MO USA.
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  • Ralf Baron, Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany.
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  • Robert H Dworkin, Departments of Anesthesiology and Perioperative Medicine, Neurology, and Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
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  • Ian Gilron, Department of Anesthesiology & Perioperative Medicine, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.
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  • Maija Haanpaa, Ilmarinen Mutual Insurance Company, Helsinki, Finland.
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  • Troels S Jensen
  • Peter R Kamerman, Brain Function Research Group, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
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  • Ewan McNicol, Tufts Medical Center, Departments of Pharmacy and Anesthesiology & Perioperative Medicine, and Tufts University School of Medicine, Boston MA, USA.
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  • Andrew Moore, Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Pain Research, The Churchill, Oxford, UK.
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  • Srinivasa N Raja, Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, USA.
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  • Niels T Andersen
  • Emily S Sena, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh
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  • Blair H Smith, Division of Population Health Sciences, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD2 4BF, Scotland.
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  • Andrew Sc Rice, Pain Research, Department of Surgery and Cancer, Imperial College, London, United Kingdom.
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  • Nadine Attal, INSERM U-987, Centre d'Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne-Billancourt, France.

Multiple recent pharmacological clinical trials in neuropathic pain have failed to show beneficial effect of drugs with previously demonstrated efficacy, and estimates of drug efficacy seems to have decreased with accumulation of newer trials. However, this has not been systematically assessed. Here we analyze time-dependent changes in estimated treatment effect size in pharmacological trials together with factors that may contribute to decreases in estimated effect size. This study is a secondary analysis of data from a previous published NeuPSIG systematic review and meta-analysis, updated to include studies published up till March 2017. We included double-blind, randomized, placebo-controlled trials examining the effect of drugs for which we had made strong or weak recommendations for use in neuropathic pain in the previously published review. As the primary outcome, we used an aggregated number needed to treat (NNT) for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. NNT values increased from around 2-4 in trials published between 1982 and 1999 to much higher (less effective) values in studies published from 2010 onwards. Several factors that changed over time, such as larger study size, longer study duration, and more studies reporting 50% or 30% pain reduction correlated with the decrease in estimated drug effect sizes. This suggests that issues related to the design, outcomes and reporting have contributed to changes in the estimation of treatment effects. These factors are important to consider in design and interpretation of individual study data and in systematic reviews and meta-analyses.

Original languageEnglish
Pages (from-to)2339-2346
Publication statusPublished - Nov 2018

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