Meta-Analysis

. 2025 May;24(5):413-428.

doi: 10.1016/S1474-4422(25)00068-7.

Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis

Nadia Soliman¹, Xavier Moisset², Michael C Ferraro³, Daniel Ciampi de Andrade⁴, Ralf Baron⁵, Joletta Belton⁶, David L H Bennett⁷, Margarita Calvo⁸, Patrick Dougherty⁹, Ian Gilron¹⁰, Aki J Hietaharju¹¹, Koichi Hosomi¹², Peter R Kamerman¹³, Harriet Kemp¹⁴, Elena K Enax-Krumova¹⁵, Ewan McNicol¹⁶, Theodore J Price¹⁷, Srinivasa N Raja¹⁸, Andrew S C Rice¹⁴, Blair H Smith¹⁹, Fiona Talkington²⁰, Andrea Truini²¹, Jan Vollert²², Nadine Attal²³, Nanna B Finnerup²⁴, Simon Haroutounian²⁵; NeuPSIG Review Update Study Group

Collaborators, Affiliations

Collaborators

NeuPSIG Review Update Study Group:
Ramla Abuukar Abdullahi, Matthew Evans, Sascha Freigang, Bethany Gwyther, Gabriel Taricani Kubota, Jules Phalip, Harrison Phillips, Cristina Ramirez Piriz, Tjokorda Istri Pramitasuri, Augustus Rottenberg, David Hohenschurz-Schmidt, Nina Tau-Lim, Queyn V Than, Jan D Wandrey, Claire Wang, Andreas Zachariadis, Mohammad D Zunaid

Affiliations

¹ Pain Research Group, Department of Surgery and Cancer, Imperial College London, London, UK. Electronic address: n.soliman16@imperial.ac.uk.
² Université Clermont Auvergne, CHU Clermont-Ferrand, Inserm, Neuro-Dol, Clermont-Ferrand, France.
³ Centre for Pain IMPACT, Neuroscience Research Australia, Australia; School of Health Sciences, Faculty of Medicine and Health, University of New South Wales Sydney, NSW, Australia).
⁴ Center for Neuroplasticity and Pain, Health Science and Technology Department, Faculty of Medicine, Aalborg University, Denmark.
⁵ Division of Neurological Pain Research and Therapy, Department of Neurology, Christian-Albrechts-University, Kiel, Germany.
⁶ Fraser, CO, USA.
⁷ The Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
⁸ Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile; Anesthesiology Division, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁹ Department of Pain Medicine, MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada; Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada; School of Policy Studies, Queen's University, Kingston, ON, Canada; Kingston Health Sciences Centre, Providence Care Hospital, Kingston, ON, Canada.
¹¹ Department of Neurology, Tampere University Hospital, Tampere, Finland.
¹² Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan.
¹³ Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, South Africa.
¹⁴ Pain Research Group, Department of Surgery and Cancer, Imperial College London, London, UK.
¹⁵ Department of Neurology, BG University Hospital Bergmannsheil, Ruhr University Bochum, Germany.
¹⁶ Department of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA.
¹⁷ Center for Advanced Pain Studies, Richardson, TX, USA; Department of Neuroscience, University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, USA.
¹⁸ Departments of Anesthesiology and Critical Care Medicine and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁹ Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK.
²⁰ Reading, UK.
²¹ Department of Human Neuroscience, Sapienza University, Rome, Italy.
²² Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
²³ Inserm U987, APHP, UVSQ Paris Saclay University, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
²⁴ Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²⁵ Department of Anesthesiology, Washington University in St Louis School of Medicine, St Louis, MO, USA.

PMID: 40252663
DOI: 10.1016/S1474-4422(25)00068-7

Free article

Meta-Analysis

Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis

Nadia Soliman et al. Lancet Neurol. 2025 May.

Free article

. 2025 May;24(5):413-428.

doi: 10.1016/S1474-4422(25)00068-7.

Authors

Collaborators

NeuPSIG Review Update Study Group:
Ramla Abuukar Abdullahi, Matthew Evans, Sascha Freigang, Bethany Gwyther, Gabriel Taricani Kubota, Jules Phalip, Harrison Phillips, Cristina Ramirez Piriz, Tjokorda Istri Pramitasuri, Augustus Rottenberg, David Hohenschurz-Schmidt, Nina Tau-Lim, Queyn V Than, Jan D Wandrey, Claire Wang, Andreas Zachariadis, Mohammad D Zunaid

Affiliations

¹ Pain Research Group, Department of Surgery and Cancer, Imperial College London, London, UK. Electronic address: n.soliman16@imperial.ac.uk.
² Université Clermont Auvergne, CHU Clermont-Ferrand, Inserm, Neuro-Dol, Clermont-Ferrand, France.
³ Centre for Pain IMPACT, Neuroscience Research Australia, Australia; School of Health Sciences, Faculty of Medicine and Health, University of New South Wales Sydney, NSW, Australia).
⁴ Center for Neuroplasticity and Pain, Health Science and Technology Department, Faculty of Medicine, Aalborg University, Denmark.
⁵ Division of Neurological Pain Research and Therapy, Department of Neurology, Christian-Albrechts-University, Kiel, Germany.
⁶ Fraser, CO, USA.
⁷ The Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
⁸ Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile; Anesthesiology Division, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁹ Department of Pain Medicine, MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada; Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada; School of Policy Studies, Queen's University, Kingston, ON, Canada; Kingston Health Sciences Centre, Providence Care Hospital, Kingston, ON, Canada.
¹¹ Department of Neurology, Tampere University Hospital, Tampere, Finland.
¹² Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan.
¹³ Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, South Africa.
¹⁴ Pain Research Group, Department of Surgery and Cancer, Imperial College London, London, UK.
¹⁵ Department of Neurology, BG University Hospital Bergmannsheil, Ruhr University Bochum, Germany.
¹⁶ Department of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA.
¹⁷ Center for Advanced Pain Studies, Richardson, TX, USA; Department of Neuroscience, University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, USA.
¹⁸ Departments of Anesthesiology and Critical Care Medicine and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁹ Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK.
²⁰ Reading, UK.
²¹ Department of Human Neuroscience, Sapienza University, Rome, Italy.
²² Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
²³ Inserm U987, APHP, UVSQ Paris Saclay University, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
²⁴ Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²⁵ Department of Anesthesiology, Washington University in St Louis School of Medicine, St Louis, MO, USA.

PMID: 40252663
DOI: 10.1016/S1474-4422(25)00068-7

Abstract

Background: There remains a substantial unmet need for effective and safe treatments for neuropathic pain. The Neuropathic Pain Special Interest Group aimed to update treatment recommendations, published in 2015, on the basis of new evidence from randomised controlled trials, emerging neuromodulation techniques, and advances in evidence synthesis.

Methods: For this systematic review and meta-analysis, we searched Embase, PubMed, the International Clinical Trials Registry, and ClinicalTrials.gov from data inception for neuromodulation trials and from Jan 1, 2013, for pharmacological interventions until Feb 12, 2024. We included double-blind, randomised, placebo-controlled trials that evaluated pharmacological and neuromodulation treatments administered for at least 3 weeks, or if there was at least 3 weeks of follow-up, and which included at least ten participants per group. Trials included participants of any age with neuropathic pain, defined by the International Association for the Study of Pain. We excluded trials with enriched enrolment randomised withdrawal designs and those with participants with mixed aetiologies (ie, neuropathic and non-neuropathic pain) and conditions such as complex regional pain syndrome, low back pain without radicular pain, fibromyalgia, and idiopathic orofacial pain. We extracted summary data in duplicate from published reports, with discrepancies reconciled by a third independent reviewer on the platform Covidence. The primary efficacy outcome was the proportion of responders (50% or 30% reduction in baseline pain intensity or moderate pain relief). The primary safety outcome was the number of participants who withdrew from the treatment owing to adverse events. We calculated a risk difference for each comparison and did a random-effects meta-analysis. Risk differences were used to calculate the number needed to treat (NNT) and the number needed to harm (NNH) for each treatment. Risk of bias was assessed by use of the Cochrane risk of bias tool 2 and certainty of evidence assessed by use of GRADE. Recommendations were based on evidence of efficacy, adverse events, accessibility, and cost, and feedback from engaged lived experience partners. This study is registered on PROSPERO, CRD42023389375.

Findings: We identified 313 trials (284 pharmacological and 29 neuromodulation studies) for inclusion in the meta-analysis. Across all studies, 48 789 adult participants were randomly assigned to trial groups (20 611 female and 25 078 male participants, where sex was reported). Estimates for the primary efficacy and safety outcomes were tricyclic antidepressants (TCAs) NNT=4·6 (95% CI 3·2-7·7), NNH=17·1 (11·4-33·6; moderate certainty of evidence), α2δ-ligands NNT=8·9 (7·4-11·10), NNH=26·2 (20·4-36·5; moderate certainty of evidence), serotonin and norepinephrine reuptake inhibitors (SNRIs) NNT=7·4 (5·6-10·9), NNH=13·9 (10·9-19·0; moderate certainty of evidence), botulinum toxin (BTX-A) NNT=2·7 (1·8-9·61), NNH=216·3 (23·5-∞; moderate certainty of evidence), capsaicin 8% patches NNT=13·2 (7·6-50·8), NNH=1129·3 (135·7-∞; moderate certainty of evidence), opioids NNT=5·9 (4·1-10·7), NNH=15·4 (10·8-24·0; low certainty of evidence), repetitive transcranial magnetic stimulation (rTMS) NNT=4·2 (2·3-28·3), NNH=651·6 (34·7-∞; low certainty of evidence), capsaicin cream NNT=6·1 (3·1-∞), NNH=18·6 (10·6-77·1; very low certainty of evidence), lidocaine 5% plasters NNT=14·5 (7·8-108·2), NNH=178·0 (23·9-∞; very low certainty of evidence). The findings provided the basis for a strong recommendation for use of TCAs, α2δ-ligands, and SNRIs as first-line treatments; a weak recommendation for capsaicin 8% patches, capsaicin cream, and lidocaine 5% plasters as second-line recommendation; and a weak recommendation for BTX-A, rTMS, and opioids as third-line treatments for neuropathic pain.

Interpretation: Our results support a revision of the Neuropathic Pain Special Interest Group recommendations for the treatment of neuropathic pain. Treatment outcomes are modest and for some treatments uncertainty remains. Further large placebo-controlled or sham-controlled trials done over clinically relevant timeframes are needed.

Funding: NeuPSIG and ERA-NET Neuron.

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Conflict of interest statement

Declaration of interests XM has received personal fees from Allergan-AbbVie, Aptis Pharma, Biogen, BMS, Grünenthal, Haute Autorité de Santé, Lilly, Lundbeck, Teva, Merck-Serono, Novartis, Orion, Pfizer, Roche, and Sanofi-Genzyme; grants from APICIL, region Auvergne-Rhone-Alpes, contrat Interface Inserm; and non-financial support from SOS Oxygène, unrelated to the submitted work. DCdA reports being vice-chair, research committee of the European Federation of IASP chapters, section editor European Journal of Pain, and being on the advisory board Pain Reports; is an employee of Aalborg Universitet, Denmark; is a non-remunerated collaborator professor of the University of Sao Paulo, Brazil; received institutional investigator-initiated research grants from Cristalia, Mundipharma, Saint Jude–Abbott Medical, Medtronic, Magventure, Grunenthal; gave remunerated lectures for Mundipharma, GreenCare, and Magventure; received conference travel support from the Pain Center University of Sao Paulo, Brazil, and Megventure; received a research grant from Fundacao de Amparo à Pesquisa do Estado de Sao Paulo, Brazil), the Novo Nordisk Foundation, Neuroscience Academy Denmark (Lundbeck Foundation), Horizon Europe (Fresco4NoPain European consortium), and the EU European Research Council. RB has financial interest of affiliation with the following organisations that could be perceived as a real or apparent competing interest. Grant or research support: EU Projects: Europain (115007); DOLORisk (633491) and IMI Paincare (777500); German Federal Ministry of Education and Research, Verbundprojekt—Frühdetektion von Schmerzchronifizierung (NoChro) (13GW0338C); German Research Network on Neuropathic Pain (01EM0903); Pfizer Pharma, Grünenthal GmbH, Mundipharma Research, Alnylam Pharmaceuticals, Zambon, Sanofi Aventis GmbH, Viatris; Speaker: Pfizer Pharma, Sanofi Aventis, Grünenthal, Mundipharma, Lilly, Desitin Arzneimittel, Teva, Bayer, MSD, Seqirus Australia, Novartis Pharma, TAD Pharma, Grünenthal Portugal, Grünen-thal Pharma Schweiz, Grünenthal Niederlande, Evapharma, Takeda Pharmaceuticals International Schweiz, Ology Medical Education Netherlands, Ever Pharma, Amicus Therapeutics, Novo Nordisk Pharma, Chiesi, Stada Mena Dubai, Hexal, Viatris, AstraZeneca, and Sandoz. Consultant: Pfizer Pharma, Sanofi Aventis, Grünenthal, Lilly, Novartis Pharma, Bristol-Myers Squibb, Biogenidec, AstraZeneca, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus Australia, Teva Pharmaceuticals Europe Niederlande, Teva, Genentech, Mundipharma International, Galapagos, Kyowa Kirin, Vertex Pharmaceuticals, Biotest, Celgene, Desitin Arzneimittel, Regeneron Pharmaceuticals USA, Theranexus Frankreich, Abbott Products Operations Schweiz, Bayer, Grünenthal Pharma Schweiz, Akcea Therapeutics Germany, Asahi Kasei Pharma, AbbVie Deutschland, Air Liquide Sante International Frankreich, Alnylam Germany, Lateral Pharma, Hexal, Angelini, Janssen, SIMR Biotech Australia, Confo Therapeutics Belgium, Merz Pharmaceuticals, Neumentum, F Hoffmann-La Roche Switzerland, AlgoTherapeutix France, Nanobiotix France, AmacaThera Canada, Heat2Move, Resano, Esteve Pharmaceuticals, Aristo, Viatris. DLHB has been a consultant for 5 am ventures, AditumBio, Astra Zeneca, Biogen, Biointervene, Combigene, LatigoBio, GSK, Ionis, Lexicon therapeutics, Neuvati, Novo Ventures, Olipass, Orion, Replay, SC Health Managers, Third Rock ventures, and Vida Ventures, Vertex on behalf of Oxford University Innovation; has received research funding from Lilly and Astra Zeneca; has received an industrial partnership grant from the BBSRC and AstraZeneca; has received funding from EU Projects: “Europain” (115007) and DOLORisk (633491); and has received funding from Wellcome Trust, the Medical Research Council, Versus Arthritis and Diabetes UK. IG has received support from Vertex and Combigene, and has received grants from the Canadian Institutes of Health Research, Physicians’ Services Incorporated Foundation, and Queen's University. EM declares no competing interests. AJH has received lecture fees from Sanofi, Teva, Takeda, Merck, Pfizer, Lundbeck, CSL Behring, Fresenius Kabi, Alexion Pharmaceuticals, MSD, Otsuka Pharmaceutical, and Novartis Finland. He has received research funding from Alnylam and Sanofi-Genzyme. He has acted as a consultant for Sanofi and Takeda. KH has received lecture fees, consulting fees, and contract research funds from Daiichi Sankyo, lecture fees from Medtronic Japan, Boston Scientific Japan, Nippon Zoki Pharmaceutical, and Mikasa Seiyaku, consulting fees from Teijin Pharma, Araya, and the Japanese Society of Psychiatry and Neurology, travel expenses from Integra Japan, and grants from the Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, and Taiju Life Social Welfare Foundation. HK has received funding from the National Institute for Health & Care Research, UK for a Clinical Lectureship (Feb, 2019–Jan, 2024) and the Academy of Medical Sciences for unrelated projects. EKE-K holds an endowed professorship funded by the German Social Accident Insurance for a period of 6 years and has received intramural funding from the Medical Faculty of the Ruhr University Bochum (grant number IF-031-22), from the Georg Agricola Ruhr Foundation as well as from the Bundesministerium für Wirtschaft und Technologie (grant number 50WK2273B) and has also received personal fees from Novartis, Casquar GmbH, OmegaPharma, and painCert. TJP is a co-founder of 4E Therapeutics, PARMedics, Nerveli, NuvoNuro, and Doloromics. He has received consulting fees from GSK, ADARx, Grunenthal, and Gordian. He holds or has held research grants or contracts with Hoba Therapeutics, Bellus Health, Merck, Eli Lilly, Evommune, Abbvie, and National Institutes of Health, USA. SNR is a consultant for Abbvie and Vertex. ASCR declares the following (last 36 months): Officer of IASP; employee of Imperial College London; consultancy for Imperial College Consultants- has included remunerated work for: Astra Zeneca, Pharmnovo, Confo, Combigene, and Shanghai SIMR Biotech & Science Practice (Wellcome Trust); inventor on patents WO 2005/079771 & EP13702262.0/ WO2013 110945. Member Joint Committee on Vaccine and Immunisation—varicella sub-committee; Analgesic Clinical Trial Translation: Innovations, Opportunities, and Networks steering committee member. Medicines and Healthcare products Regulatory Agency, Commission on Human Medicines—Neurology, Pain & Psychiatry Expert Advisory Group. Grants and studentships—UK Research and Innovation (Medical Research Council and Biotechnology and Biological Sciences Research Council), Versus Arthritis, Alan and Sheila Diamond Trust, Royal British Legion, European Commission, Ministry of Defence, Dr Jennie Gwynn Bequests, The British Pain Society, Royal Society of Medicine Lecture honoraria (some donated to charity); MD Cancer Center, University California San Francisco; BIOEVENTS, Royal Marsden Hospital, Indonesian Neurological Association Pain Study Group International Lecture Series, Malaysian Society of Anaesthesiologists, Siriraj Hospital (Bangkok), Pain Association of Singapore, Hospital for Special Surgery (New York). DH-S has received grant funding from the Alan and Sheila Diamond Charitable Trust, The Society for Back Pain Research, and Chelsea and Westminster Hospital Joint Research Council; and consultancy fees from Altern Health for unrelated projects. BHS has received, on behalf of his institution, research funding from Eli Lilly, unrelated to the submitted work. AT has acted as a consultant for Amgen, Viatris, Angelini Pharma, Grunenthal GmbH; he has received research funding from Angelini Pharma and Epitech and has received funding from the EU Project IMI-PainCare (777500). JV has received research funding or consultancy fees from Viatris, AstraZeneca, and Merz, unrelated to the submitted work. JDW is a fellow of the Berlin Institute of Health (BIH) Charité Digital Clinician Scientist (DCSP) Program funded by the DFG, the Charité—Universitätsmedizin Berlin, and the BIH at Charité; he received travel funding by the BIH DCSP Mobility Funds and the German Pain Society (Deutsche Schmerzgesellschaft). NA has received personal fees from Grunenthal, UPSA, Pfizer, Merz, Medtronic, Novartis, Viatris outside the submitted work and is member of the Dolorisk, HaPPy and Fresco4Pain European consortia. NBF has received consultancy fees from PharmNovo, Vertex, NeuroPN, Saniona, Nanobiotix, and Neurvati, and has done consultancy work for Aarhus University with remunerated work for Biogen, Merz, and Confo Therapeutics; she has received grants from IMI2PainCare an EU IMI 2 (Innovative medicines initiative) and the companies involved are Grunenthal, Bayer, Eli Lilly, Esteve, and Teva, outside the submitted work. SH has received research grants from the US National Institutes of Health and Department of Defense, as well as from Eli Lilly, outside the submitted work. He has received consultancy fees from Vertex. NS, MCF, RAA, JB, MC, PD, ME, SF, BG, PRK, GTK, EW, JP, HP, CRP, TIPi, AR, FT, NT-L, QVT, CW, AZ, and MDZ have no competing interests to declare.

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Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis

Collaborators

Affiliations

Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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