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 for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. Number needed to treat values increased from around 2 to 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.
aDepartment of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark
bDepartment of Neurology, Aarhus University Hospital, Aarhus, Denmark
cDivision of Clinical and Translational Research, Department of Anesthesiology, Pain Center, Washington University in St. Louis School of Medicine, St Louis, MO, United States
dDivision of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany
Departments of eAnesthesiology and Perioperative Medicine
gPsychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
hDepartment of Anesthesiology and Perioperative Medicine, Queen's University and Kingston General Hospital, Kingston, ON, Canada
iIlmarinen Mutual Insurance Company, Helsinki, Finland
jBrain Function Research Group, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
kSchool of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Australia
Departments of lPharmacy and
mAnesthesiology and Perioperative Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston MA, United States
nNuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Pain Research, University of Oxford, The Churchill, Oxford, United Kingdom
oDivision of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
pNT Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark
qCentre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
rDivision of Population Health Sciences, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland
sPain Research, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
tINSERM U-987, Centre d'Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne-Billancourt, France
Corresponding author. Address: Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Denmark Building 1A, Norrebrogade 44, DK-8000 Aarhus C, Denmark. Tel.: +45 78464230; fax: +45 78463287. E-mail address: email@example.com (N.B. Finnerup).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
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A.S.C. Rice and N. Attal contributed equally to this work.
Received February 06, 2018
Received in revised form June 22, 2018
Accepted July 05, 2018