Nanna B Finnerup1, Nadine Attal2, Simon Haroutounian3, Ewan McNicol4, Ralf Baron5, Robert H Dworkin6, Ian Gilron7, Maija Haanpää8, Per Hansson9, Troels S Jensen10, Peter R Kamerman11, Karen Lund1, Andrew Moore12, Srinivasa N Raja13, Andrew S C Rice14, Michael Rowbotham15, Emily Sena16, Philip Siddall17, Blair H Smith18, Mark Wallace19. 1. Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. 2. INSERM U-987, Centre d'Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne-Billancourt, France; Université Versailles Saint-Quentin, France. Electronic address: nadine.attal@apr.aphp.fr. 3. Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA. 4. Departments of Anesthesiology and Pharmacy, Tufts Medical Center, Boston, MA, USA. 5. Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany. 6. Department of Anesthesiology and Department of Neurology, Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. 7. Department of Anesthesiology and Perioperative Medicine and Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. 8. Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland; Mutual Insurance Company Etera, Helsinki, Finland. 9. Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 10. Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark. 11. Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, South Africa. 12. Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Pain Research, Churchill Hospital, Oxford, UK. 13. Johns Hopkins School of Medicine, Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Baltimore, MD, USA. 14. Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, UK; Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. 15. California Pacific Medical Center Research Institute and UCSF Pain Management Center, San Francisco, CA, USA. 16. Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. 17. Department of Pain Management, Greenwich Hospital, HammondCare, Sydney, NSW, Australia; Kolling Institute, Sydney Medical School-Northern, University of Sydney, Sydney, NSW, Australia. 18. Division of Population Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland. 19. Division of Pain Medicine, Department of Anesthesiology, UCSD, San Diego, CA, USA.
Abstract
BACKGROUND: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. METHODS: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. FINDINGS: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. INTERPRETATION: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. FUNDING: NeuPSIG of the International Association for the Study of Pain.
BACKGROUND: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. METHODS: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. FINDINGS: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. INTERPRETATION: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. FUNDING: NeuPSIG of the International Association for the Study of Pain.
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