{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:09:29Z","timestamp":1789168169564,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) conducted from January 2005 to June 2021 to update the evidence of Botulinum toxin A (BoNT-A) in neuropathic pain (NP) in addition to quality of life (QOL), mental health, and sleep outcomes. We conducted a Cochrane Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria analysis of RCTs from the following data sources: EMBASE, CINAHL, WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, Cochrane database, Cochrane Clinical Trial Register, Australia New Zealand Clinical Trials Registry, and EU Clinical Trials Register. Meta-analysis of 17 studies showed a mean final VAS reduction in pain in the intervention group of 2.59 units (95% confidence interval: 1.79, 3.38) greater than the mean for the placebo group. The overall mean difference for sleep, Hospital Anxiety and Depression Scale (HADS) anxiety, HADS depression, and QOL mental and physical sub-scales were, respectively, 1.10 (95% CI: \u22121.71, 3.90), 1.41 (95% CI: \u22120.61, 3.43), \u22120.16 (95% CI: \u22121.95, 1.63), 0.85 (95% CI: \u22121.85, 3.56), and \u22120.71 (95% CI: \u22123.39, 1.97), indicating no significance. BoNT-A is effective for NP; however, small-scale RCTs to date have been limited in evidence. The reasons for this are discussed, and methods for future RCTs are developed to establish BoNT-A as the first-line agent.<\/jats:p>","DOI":"10.3390\/toxins14010036","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T23:35:09Z","timestamp":1641771309000},"page":"36","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["A Systematic Review and Meta-Analysis of Efficacy of Botulinum Toxin A for Neuropathic Pain"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5182-6919","authenticated-orcid":false,"given":"Anupam","family":"Datta Gupta","sequence":"first","affiliation":[{"name":"Central Adelaide Rehabilitation Services, Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Edwards","sequence":"additional","affiliation":[{"name":"Adelaide Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Smith","sequence":"additional","affiliation":[{"name":"Central Adelaide Rehabilitation Services, Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Snow","sequence":"additional","affiliation":[{"name":"Lyell McEwin Hospital, Northern Adelaide Local Health Network, Adelaide, SA 5112, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1303-9479","authenticated-orcid":false,"given":"Renuka","family":"Visvanathan","sequence":"additional","affiliation":[{"name":"National Health and Medical Research Council Centre of Research Excellence in Frailty and Healthy Aging, Basil Hetzel Institute, 28 Woodville Road, Adelaide, SA 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2621-5942","authenticated-orcid":false,"given":"Graeme","family":"Tucker","sequence":"additional","affiliation":[{"name":"National Health and Medical Research Council Centre of Research Excellence in Frailty and Healthy Aging, Basil Hetzel Institute, 28 Woodville Road, Adelaide, SA 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Wilson","sequence":"additional","affiliation":[{"name":"National Health and Medical Research Council Centre of Research Excellence in Frailty and Healthy Aging, Basil Hetzel Institute, 28 Woodville Road, Adelaide, SA 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S127","DOI":"10.1097\/j.pain.0000000000001824","article-title":"Neuropathic pain in the community: Prevalence, impact, and risk factors","volume":"161","author":"Smith","year":"2020","journal-title":"Pain"},{"key":"ref_2","first-page":"537","article-title":"GP pain management: What are the P\u2019s and A\u2019s of pain management","volume":"43","author":"Wan","year":"2014","journal-title":"Aust. Fam. Physician"},{"key":"ref_3","first-page":"167","article-title":"Chronic Pain: Where the Body Meets the Brain","volume":"126","author":"Crofford","year":"2015","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1111\/j.1525-1497.2006.00412.x","article-title":"Primary care provider concerns about management of chronic pain in community clinic populations","volume":"21","author":"Upshur","year":"2006","journal-title":"J. Gen. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"802893","DOI":"10.1155\/2012\/802893","article-title":"Therapeutic Use of Botulinum Toxin in Neurorehabilitation","volume":"2012","author":"Intiso","year":"2012","journal-title":"J. Toxicol."},{"key":"ref_6","first-page":"1","article-title":"Therapeutic uses of botulinum toxin","volume":"5","author":"Gooriah","year":"2015","journal-title":"J. Clin. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1124\/pr.116.012658","article-title":"Botulinum neurotoxins: Biology, pharammcologyand toxicology","volume":"69","author":"Pirazzini","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1212\/01.wnl.0000345968.05959.cf","article-title":"Botulinum toxin for diabetic neuropathic pain: A randomized double-blind crossover trial","volume":"72","author":"Yuan","year":"2009","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1136\/jnnp.2006.103341","article-title":"Treatment of shoulder pain in spastic hemiplegia by reducing spasticity of the subscapular muscle: A randomised, double blind, placebo controlled study of botulinum toxin A","volume":"78","author":"Yelnik","year":"2007","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"440","DOI":"10.2340\/16501977-0066","article-title":"Is Botulinum Toxin Type A Effective in The Treatment of Spastic Shoulder Pain in Patients After Stroke Unclear Risk. A Double-blind Randomized Clinical Trial","volume":"39","author":"Marco","year":"2007","journal-title":"J. Rehabil. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1177\/0269215506072082","article-title":"A randomized controlled study of botulinum toxin A in the treatment of hemiplegic shoulder pain associated with spasticity","volume":"21","author":"Kong","year":"2007","journal-title":"Clin. Rehabil."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1161\/STROKEAHA.107.484048","article-title":"Intramuscular Botulinum Toxin-A Reduces Hemiplegic Shoulder Pain","volume":"39","author":"Lim","year":"2008","journal-title":"Stroke"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1002\/ana.21427","article-title":"Botulinum toxin type a induces direct analgesic effects in chronic neuropathic pain","volume":"64","author":"Ranoux","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1111\/j.1526-4637.2010.01003.x","article-title":"Subcutaneous Injection of Botulinum Toxin A Is Beneficial in Postherpetic Neuralgia","volume":"11","author":"Xiao","year":"2010","journal-title":"Pain Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/j.pain.2011.04.027","article-title":"Botulinum toxin injection for management of thoracic thoracic outlet syndrome: A double-blind, randomized trial","volume":"152","author":"Finlayson","year":"2011","journal-title":"Pain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1177\/0333102412441721","article-title":"Botulinum toxin type A for the treatment of trigeminal neuralgia: Results from a randomized, double-blind, placebo-controlled trial","volume":"32","author":"Wu","year":"2012","journal-title":"Cephalalgia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/1129-2377-14-92","article-title":"Botulinum toxin-type A: Could it be an effective treatment option in intractable trigeminal neuralgia?","volume":"19","author":"Shehata","year":"2013","journal-title":"J. Headache Pain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1097\/AJP.0b013e31827a72d2","article-title":"Botulinum Toxin A in Postherpetic Neuralgia A Parallel, Randomized, Double-Blind, Single-Dose, Placebo-controlled Trial","volume":"29","author":"Apalla","year":"2013","journal-title":"Clin. J. Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/WNF.0b013e31829cb60e","article-title":"Acute Treatment of Trigeminal Neuralgia With Onabotulinum Toxin A","volume":"36","author":"Piedimonte","year":"2013","journal-title":"Clin. Neuropharmacol."},{"key":"ref_20","first-page":"106","article-title":"The effects of intradermal botulinum toxin type a injections on pain symptoms of patients with diabetic neuropathy","volume":"19","author":"Ghasemi","year":"2014","journal-title":"J. Res. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/1129-2377-15-65","article-title":"Two doses of botulinum toxin type A for the treatment of trigeminal neuralgia: Observation of therapeutic effect from a randomized, double-blind, placebo-controlled trial","volume":"15","author":"Zhang","year":"2014","journal-title":"J. Headache Pain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/ana.24605","article-title":"Botulinum toxin type A for neuropathic pain in patients with spinal cord injury","volume":"79","author":"Han","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S1474-4422(16)00017-X","article-title":"Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): A randomised, double-blind, placebo-controlled trial","volume":"15","author":"Attal","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/mus.25504","article-title":"Electro physiologically identified piriformis syndrome is successfully treated with incobotulinum toxin and physical therapy","volume":"56","author":"Fishman","year":"2017","journal-title":"Muscle Nerve"},{"key":"ref_25","first-page":"99","article-title":"The effects of botulinum toxin type A injection on pain symptoms, quality of life, and sleep quality of patients with diabetic neuropathy: A randomized double-blind clinical trial","volume":"18","author":"Salehi","year":"2019","journal-title":"Iran. J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1016\/j.dsx.2020.09.019","article-title":"The Effect of Intradermal Botulinum Toxin a injections on painful diabetic polyneuropathy","volume":"14","author":"Taheri","year":"2020","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.2147\/JPR.S168650","article-title":"Botulinum toxin-A for the treatment of neuralgia: A systematic review and meta-analysis","volume":"11","author":"Meng","year":"2018","journal-title":"J. Pain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.oooo.2016.03.003","article-title":"The efficacy of botulinum toxin for the treatment of trigeminal ad postherpetic neuralgia: A systematic review with meta-analyses","volume":"19","author":"Shackleton","year":"2016","journal-title":"Oral Surgery Oral Med. Oral Path. Oral Rad."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s10194-016-0651-8","article-title":"Therapeutic efficacy and safety of botulinum toxin A therapy in trigeminal neuralgia: A systematic review and meta-analysis of randomised controlled trials","volume":"17","author":"Morra","year":"2016","journal-title":"J. Headache Pain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1185\/030079904125003962","article-title":"Safety of botulinum toxin type A: A systematic review and meta-analysis","volume":"20","author":"Nauman","year":"2004","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e027953","DOI":"10.1136\/bmjopen-2018-027953","article-title":"Cochrane systematic review and meta-analysis of botulinum toxin for the prevention of migraine","volume":"9","author":"Herd","year":"2019","journal-title":"BMJ Open"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1111\/pme.12728","article-title":"Botulinum Toxin-A for Painful Diabetic Neuropathy: A Meta-Analysis","volume":"16","author":"Lakhan","year":"2015","journal-title":"Pain Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e01409","DOI":"10.1002\/brb3.1409","article-title":"The efficacy and safety of botulinum toxin type A treatment of trigeminal neuralgia and peripheral neuropathic pain: A meta-analysis of randomised controlled trails","volume":"9","author":"Wei","year":"2019","journal-title":"Brain Behav."},{"key":"ref_34","unstructured":"(2021, November 20). NHMRC Levels of Evidence and Grades for Recommendations for Developers of Guidelines, Available online: https:\/\/www.nhmrc.gov.au\/sites\/default\/files\/images\/NHMRC%20Levels%20and%20Grades%20(2009).pdf."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.jclinepi.2010.04.026","article-title":"GRADE guidelines: 1. Introduction\u2014GRADE evidence profiles and summary of findings tables","volume":"64","author":"Guyatt","year":"2011","journal-title":"J. Clin. Epidemiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_37","first-page":"973","article-title":"Assessing the quality of randomised controlled trails of complex regional pain syndrome published in the Journal of Clinical Pain Medicine Field","volume":"27","author":"Lee","year":"2012","journal-title":"J. Korean Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"716","DOI":"10.3389\/fneur.2020.00716","article-title":"Botulinum Neurotoxin for the Treatment of Neuropathic Pain","volume":"11","author":"Egeo","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"379","DOI":"10.5694\/mja17.00841","article-title":"Spasticity\/Dystonia\u2014Current Pharmaceutical Benefits Scheme-Guidelines for Treatment with Botulinum Toxin\u2014A Case for Change","volume":"208","author":"Wilson","year":"2018","journal-title":"Med. J. Aust."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.bja.2017.11.098","article-title":"\u201cPain as the fifth vital sign\u201d and dependence on the \u201cnumerical pain scale\u201d is being abandoned in the US: Why?","volume":"120","author":"Levy","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.neuint.2012.05.001","article-title":"Botulinum toxin\u2019s axonal transport properties from periphery to spinal cord","volume":"61","author":"Matak","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"d4002","DOI":"10.1136\/bmj.d4002","article-title":"Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials","volume":"343","author":"Sterne","year":"2011","journal-title":"BMJ"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"BMJ"},{"key":"ref_44","unstructured":"(2021, November 20). Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 edited by Julian PT and Sally Green. Available online: https:\/\/handbook-5-1.cochrane.org\/."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1093\/ije\/31.1.88","article-title":"Asymmetric funnel plots and publication bias in meta-analyses of diagnostic accuracy","volume":"31","author":"Song","year":"2002","journal-title":"Int. J. Epidemiol."},{"key":"ref_46","unstructured":"Diener, E., Oishi, S., and Tay, L. (2018). Re-evaluating the strengths and weaknesses of self-report measures of subjective well-being. Handbook of Well-Being, DEF Publishers. Available online: nobascholar.com."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2377-12-29","article-title":"Towards a definition of refractory neuropathic pain for epidemiological research. An international Delphi survey of experts","volume":"12","author":"Smith","year":"2012","journal-title":"BMC Neurol."},{"key":"ref_48","first-page":"310","article-title":"Measurement of pain medicine. An international Delphi Survey of Experts","volume":"16","author":"Bendiger","year":"2016","journal-title":"BJA Educ."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/14\/1\/36\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:36:02Z","timestamp":1760362562000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/14\/1\/36"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,3]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["toxins14010036"],"URL":"https:\/\/doi.org\/10.3390\/toxins14010036","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,3]]}}}