{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:19:44Z","timestamp":1783948784328,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"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>In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy of an individualized technique of subcutaneous injection of botulinum toxin type A (BoNT-A) targeted (SjBoT) to the occipital or trigeminal skin area in non-responder patients with chronic migraine (CM). Patients who had not previously responded to at least two treatments of intramuscular injections of BoNT-A were randomly assigned (2:1) to receive two subcutaneous administrations of BoNT-A (up to 200 units) with the SjBoT injection paradigm or placebo. Following the skin area where the maximum pain began, treatment was given in the trigeminal or occipital region bilaterally. The primary endpoint changed in monthly headache days from baseline to the last 4 weeks. Among 139 randomized patients, 90 received BoNT-A and 49 received placebo, and 128 completed the double-blind phase. BoNT-A significantly reduced monthly headache days versus placebo (\u221213.2 versus \u22121.2; p &lt; 0.0001) in the majority of patients who had cutaneous allodynia. Other secondary endpoints, including measures for disability (Migraine Disability Assessment questionnaire from baseline 21.96 to 7.59 after treatment, p = 0.028), also differed. Thus, in non-responder patients with CM, BoNT-A significantly reduced migraine days when administered according to the \u201cfollow the origin of maximum pain\u201d approach using SjBoT injection paradigm.<\/jats:p>","DOI":"10.3390\/toxins15050324","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T01:57:51Z","timestamp":1683683871000},"page":"324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Regional Targeted Subcutaneous Injection of Botulinum Neurotoxin Type A in Refractory Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4650-6635","authenticated-orcid":false,"given":"Francesco","family":"Bono","sequence":"first","affiliation":[{"name":"Headache Center, and Center for Botulinum Toxin Therapy, Neurology Unit, Azienda Ospedaliero-Universitaria \u201cMater Domini\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Mazza","sequence":"additional","affiliation":[{"name":"Headache Center, and Center for Botulinum Toxin Therapy, Neurology Unit, Azienda Ospedaliero-Universitaria \u201cMater Domini\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8187-8354","authenticated-orcid":false,"given":"Giuseppe","family":"Magro","sequence":"additional","affiliation":[{"name":"Headache Center, and Center for Botulinum Toxin Therapy, Neurology Unit, Azienda Ospedaliero-Universitaria \u201cMater Domini\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4417-1073","authenticated-orcid":false,"given":"Giorgio","family":"Spano","sequence":"additional","affiliation":[{"name":"Headache Center, and Center for Botulinum Toxin Therapy, Neurology Unit, Azienda Ospedaliero-Universitaria \u201cMater Domini\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Idone","sequence":"additional","affiliation":[{"name":"Headache Center, and Center for Botulinum Toxin Therapy, Neurology Unit, Azienda Ospedaliero-Universitaria \u201cMater Domini\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Laterza","sequence":"additional","affiliation":[{"name":"Headache Center, and Center for Botulinum Toxin Therapy, Neurology Unit, Azienda Ospedaliero-Universitaria \u201cMater Domini\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Tedeschi","sequence":"additional","affiliation":[{"name":"Headache Center, and Center for Botulinum Toxin Therapy, Neurology Unit, Azienda Ospedaliero-Universitaria \u201cMater Domini\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Pucci","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7384-3074","authenticated-orcid":false,"given":"Antonio","family":"Gambardella","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1362-6718","authenticated-orcid":false,"given":"Alessia","family":"Sarica","sequence":"additional","affiliation":[{"name":"Neuroscience Research Center, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/j.1468-2982.2009.01941.x","article-title":"Global prevalence of chronic migraine: A systematic review","volume":"30","author":"Natoli","year":"2010","journal-title":"Cephalalgia"},{"key":"ref_2","unstructured":"(2018). 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(2020). Botulinum Toxin in the Treatment of Headache. Toxins, 12.","DOI":"10.3390\/toxins12120803"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"K\u0119pczy\u0144ska, K., and Domitrz, I. (2022). Botulinum Toxin-A Current Place in the Treatment of Chronic Migraine and Other Primary Headaches. Toxins, 14.","DOI":"10.3390\/toxins14090619"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Baraldi, C., Lo Castro, F., Ornello, R., Sacco, S., Pani, L., and Guerzoni, S. (2023). OnabotulinumtoxinA: Still the present for chronic migraine. Toxins, 15.","DOI":"10.3390\/toxins15010059"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/ane.12171","article-title":"OnabotulinumtoxinA for chronic migraine: Efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program","volume":"129","author":"Aurora","year":"2014","journal-title":"Acta. Neurol. Scand."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1111\/head.13823","article-title":"Modifications to the PREEMPT Protocol for OnabotulinumtoxinA Injections for Chronic Migraine in Clinical Practice","volume":"60","author":"Gharedaghi","year":"2020","journal-title":"Headache"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1177\/03331024211067775","article-title":"FollowTheSutures: Piloting a new way to administer onabotulinumtoxinA for chronic migraine","volume":"42","author":"Stovner","year":"2022","journal-title":"Cephalalgia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1111\/j.1468-2982.2004.00754.x","article-title":"Botulinum toxin A in the prophylactic treatment of migraine--A randomized, double-blind, placebo-controlled study","volume":"24","author":"Evers","year":"2004","journal-title":"Cephalalgia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1093\/brain\/awz052","article-title":"Acute withdrawal and botulinum toxin A in chronic migraine with medication overuse: A double-blind randomized controlled trial","volume":"142","author":"Pijpers","year":"2019","journal-title":"Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.3390\/toxins7083127","article-title":"Botulinum Toxin for Neuropathic Pain: A Review of the Literature","volume":"7","author":"Oh","year":"2015","journal-title":"Toxins"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/S1474-4422(16)00056-9","article-title":"Fighting neuropathic pain with botulinum toxin A","volume":"15","author":"Baron","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(19)30185-1","article-title":"Migraine and the trigeminovascular system-40 years and counting","volume":"18","author":"Ashina","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.pain.2003.10.008","article-title":"Subcutaneous administration of botulinum toxin A reduces formalin-induced pain","volume":"107","author":"Cui","year":"2004","journal-title":"Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/ana.24122","article-title":"Botulinum toxin-A treatment reduces human mechanical pain sensitivity and mechanotransduction","volume":"75","author":"Paterson","year":"2014","journal-title":"Ann. 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