{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:49:23Z","timestamp":1764600563707,"version":"3.46.0"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["2023.00543.BD"],"award-info":[{"award-number":["2023.00543.BD"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006752","name":"Universidade do Porto","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006752","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neural Transm"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Botulinum toxin type A (BoNT) has emerged as a potential alternative to conventional therapies to many debilitating chronic diseases characterised by inflammatory states. However, the biological rationale remains ambiguous. Our review aimed to systematically assessed which biochemical biomarkers have been reported in clinical research to evaluate BoNT analgesic and mood-lifting effects in head and neck chronic conditions related to inflammation. We searched databases and registries between inception and September 29, 2023. Of the nine included studies, there were concerns about risk of bias for six studies. The leading biomarker with five studies was the calcitonin gene-related peptide (CGRP), followed by serotonin with two studies. Oxidative stress biomarkers were only reported in one study. Several important players in inflammatory processes and different immune cell classes have been evaluated in four studies. There was only one trial measuring changes in beta Tubulin and SNAP-25, and another study evaluating cutaneous neuropeptide substance-P. After BoNT, a significant effect was reported in six studies, including decrease in plasma levels of CGRP in chronic migraine and trigeminal neuralgia; serotonin decrease when collected from human tears in refractory intractable dry eye disease and increase in peripheral blood platelets in painful cervical dystonia associated to depression and anxiety; decrease in plasma concentration of markers of oxidative damage to proteins and increase in biomarkers for antioxidant power; decrease in expression of gene sets involved in inflammatory pathways and immune cells classes in the periosteum and metalloproteinase-9 molecule in the tears. BoNT seems to affect some biomarkers present in chronic inflammatory conditions. However, the certainty evidence found was very low to moderate. This study is registered on PROSPERO (CRD42023432131).<\/jats:p>","DOI":"10.1007\/s00702-024-02869-w","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T11:04:57Z","timestamp":1741086297000},"page":"1851-1874","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Botulinum toxin effects on biochemical biomarkers related to inflammation-associated head and neck chronic conditions: a systematic review of clinical research"],"prefix":"10.1007","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8806-3863","authenticated-orcid":false,"given":"Ines","family":"Novo Pereira","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5881-4021","authenticated-orcid":false,"given":"Sara","family":"Dur\u00e3o","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8192-9916","authenticated-orcid":false,"given":"Haidar","family":"Hassan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1991-9418","authenticated-orcid":false,"given":"Ana Cristina","family":"Braga","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4389-2825","authenticated-orcid":false,"given":"Andr\u00e9","family":"Mariz Almeida","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9881-3338","authenticated-orcid":false,"given":"Ana Cristina","family":"Manso","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9265-0913","authenticated-orcid":false,"given":"Ricardo","family":"Faria-Almeida","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0921-342X","authenticated-orcid":false,"given":"Giancarlo","family":"De la Torre Canales","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"2869_CR2","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1016\/j.jaad.2018.07.058","volume":"79","author":"KA Aschenbeck","year":"2018","unstructured":"Aschenbeck KA, Hordinsky MK, Kennedy WR, Wendelschafer-Crabb G, Ericson ME, Kavand S et al (2018) Neuromodulatory treatment of recalcitrant plaque psoriasis with onabotulinumtoxinA. J Am Acad Dermatol [internet] 79:1156\u20131159. https:\/\/doi.org\/10.1016\/j.jaad.2018.07.058","journal-title":"J Am Acad Dermatol [internet]"},{"key":"2869_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/toxins12120803","author":"WJ Becker","year":"2020","unstructured":"Becker WJ (2020) Botulinum Toxin in the Treatment of Headache. Toxins (Basel). https:\/\/doi.org\/10.3390\/toxins12120803","journal-title":"Toxins (Basel)."},{"key":"2869_CR4","doi-asserted-by":"publisher","DOI":"10.1097\/IOP.0b013e31828de9c0","author":"GE Borodic","year":"2014","unstructured":"Borodic GE, Caruso P, Acquadro M, Chick S (2014) Parry-Romberg syndrome vasculopathy and its treatment with botulinum toxin. Ophthalmic Plast Reconstr Surg. https:\/\/doi.org\/10.1097\/IOP.0b013e31828de9c0","journal-title":"Ophthalmic Plast Reconstr Surg"},{"key":"2869_CR5","doi-asserted-by":"publisher","DOI":"10.1186\/2193-1801-2-377","author":"A Bumb","year":"2013","unstructured":"Bumb A, Seifert B, Wetzel S, Agosti R (2013) Patients profiling for Botox\u00ae (onabotulinum toxin A) treatment for migraine: a look at white matter lesions in the MRI as a potential marker. Springerplus. https:\/\/doi.org\/10.1186\/2193-1801-2-377","journal-title":"Springerplus"},{"key":"2869_CR6","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1111\/head.12250","volume":"54","author":"R Cady","year":"2014","unstructured":"Cady R, Turner I, Dexter K, Beach ME, Cady R, Durham P (2014) An exploratory study of salivary calcitonin gene-related peptide levels relative to acute interventions and preventative treatment with onabotulinumtoxinA in chronic migraine. Headache 54:269\u2013277. https:\/\/doi.org\/10.1111\/head.12250","journal-title":"Headache"},{"key":"2869_CR7","doi-asserted-by":"publisher","DOI":"10.1177\/1535370217750088","author":"RM Califf","year":"2018","unstructured":"Califf RM (2018) Biomarker definitions and their applications. Exp Biol Med (Maywood). https:\/\/doi.org\/10.1177\/1535370217750088","journal-title":"Exp Biol Med (Maywood)"},{"key":"2869_CR8","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1111\/head.12372","volume":"54","author":"E Cernuda-Moroll\u00f3n","year":"2014","unstructured":"Cernuda-Moroll\u00f3n E, Mart\u00ednez-Camblor P, Ram\u00f3n C, Larrosa D, Serrano-Pertierra E, Pascual J (2014) CGRP and VIP levels as predictors of efficacy of Onabotulinumtoxin type A in chronic migraine. Headache 54:987\u2013995. https:\/\/doi.org\/10.1111\/head.12372","journal-title":"Headache"},{"key":"2869_CR9","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1097\/j.pain.0000000000000119","volume":"156","author":"E Cernuda-Moroll\u00f3n","year":"2015","unstructured":"Cernuda-Moroll\u00f3n E, Ram\u00f3n C, Mart\u00ednez-Camblor P, Serrano-Pertierra E, Larrosa D, Pascual J (2015) OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. Pain 156:820\u2013824. https:\/\/doi.org\/10.1097\/j.pain.0000000000000119","journal-title":"Pain"},{"key":"2869_CR10","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1111\/head.14224","volume":"61","author":"A Charles","year":"2021","unstructured":"Charles A, Nwaobi SE, Goadsby P (2021) Inflammation in migraine\u2026or not\u2026: A critical evaluation of the evidence. Headache 61:1575\u20131578. https:\/\/doi.org\/10.1111\/head.14224","journal-title":"Headache"},{"key":"2869_CR11","unstructured":"CASP Checklists - Critical Appraisal Skills Programme [Internet]. CASP - Critical Appraisal Skills Programme. [cited 2024 Sep 11]. https:\/\/casp-uk.net\/casp-tools-checklists\/"},{"key":"2869_CR12","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1007\/s00417-018-4194-3","volume":"257","author":"MG Choi","year":"2019","unstructured":"Choi MG, Yeo JH, Kang JW, Chun YS, Lee JK, Kim JC (2019) Effects of botulinum toxin type A on the treatment of dry eye disease and tear cytokines. Graefes Arch Clin Exp Ophthalmol [internet] 257:331\u2013338. https:\/\/doi.org\/10.1007\/s00417-018-4194-3","journal-title":"Graefes Arch Clin Exp Ophthalmol [internet]"},{"key":"2869_CR47","unstructured":"ClinicalTrials.gov [Internet]. National Library of Medicine (US). Identifier NCT01071096. Calcitonin Gene-related Peptide Levels in Chronic Migraine (Cady, Roger, M.D); 2003-02-12. [cited 2023 Oct 25]. https:\/\/clinicaltrials.gov\/study\/NCT01071096"},{"key":"2869_CR48","unstructured":"ClinicalTrials.gov [Internet]. National Library of Medicine (US). Identifier NCT02037425. Exploratory Study of the Natural History, Clinical Outcomes, and Neuronal Endplate Changes in Subjects Reporting Short Duration vs. Long Duration of Benefit for OnabotulinumtoxinA in Treatment of Chronic Migraine (Cady, Roger, M.D); 2016-08-11. [cited 2023 Oct 25]. https:\/\/clinicaltrials.gov\/study\/NCT02037425?tab=history&a=1"},{"key":"2869_CR13","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1186\/s12974-016-0738-9","volume":"13","author":"F Corrigan","year":"2016","unstructured":"Corrigan F, Mander KA, Leonard AV, Vink R (2016) Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation. J Neuroinflam 13:264. https:\/\/doi.org\/10.1186\/s12974-016-0738-9","journal-title":"J Neuroinflam"},{"key":"2869_CR14","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1111\/j.1468-2982.2006.01098.x","volume":"26","author":"F Cutrer","year":"2006","unstructured":"Cutrer F, Pittelkow M (2006) Cephalalgic alopecia areata: a syndrome of neuralgiform head pain and hair loss responsive to botulinum A toxin injection. Cephalalgia Intern J Headache 26:747\u2013751. https:\/\/doi.org\/10.1111\/j.1468-2982.2006.01098.x","journal-title":"Cephalalgia Intern J Headache"},{"key":"2869_CR15","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1111\/j.1468-2982.2009.01987.x","volume":"30","author":"FM Cutrer","year":"2010","unstructured":"Cutrer FM, Sandroni P, Wendelschafer-Crabb G (2010) Botulinum toxin treatment of cephalalgia alopecia increases substance P and calcitonin gene-related peptide-containing cutaneous nerves in scalp. Cephalalgia 30:1000\u20131006. https:\/\/doi.org\/10.1111\/j.1468-2982.2009.01987.x","journal-title":"Cephalalgia"},{"key":"2869_CR16","doi-asserted-by":"publisher","DOI":"10.3390\/toxins6020592","author":"LB da Silva","year":"2014","unstructured":"da Silva LB, Kulas D, Karshenas A, Cairns BE, Bach FW, Arendt-Nielsen L et al (2014) Time course analysis of the effects of botulinum neurotoxin type A on pain and vasomotor responses evoked by glutamate injection into human temporalis muscles. Toxins (Basel). https:\/\/doi.org\/10.3390\/toxins6020592","journal-title":"Toxins (Basel)."},{"key":"2869_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/toxins8060163","author":"M de Tommaso","year":"2016","unstructured":"de Tommaso M, Delussi M, Ricci K, Montemurno A, Carbone I, Vecchio E (2016) Effects of onabotulintoxina on habituation of laser evoked responses in chronic migraine. Toxins. https:\/\/doi.org\/10.3390\/toxins8060163","journal-title":"Toxins"},{"key":"2869_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/toxins11100608","author":"E Dini","year":"2019","unstructured":"Dini E, Mazzucchi S, De Luca C, Cafalli M, Chico L, Lo Gerfo A et al (2019) Plasma levels of oxidative stress markers, before and after BoNT\/A treatment, in chronic migraine. Toxins (Basel). https:\/\/doi.org\/10.3390\/toxins11100608","journal-title":"Toxins (Basel)."},{"key":"2869_CR19","doi-asserted-by":"publisher","DOI":"10.1111\/head.13211","author":"C Dom\u00ednguez","year":"2018","unstructured":"Dom\u00ednguez C, Vieites-Prado A, P\u00e9rez-Mato M, Sobrino T, Rodr\u00edguez-Osorio X, L\u00f3pez A et al (2018) CGRP and PTX3 as predictors of efficacy of onabotulinumtoxin Type A in chronic migraine: an observational study. Headache. https:\/\/doi.org\/10.1111\/head.13211","journal-title":"Headache"},{"key":"2869_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/toxins12080479","author":"C Dom\u00ednguez Vivero","year":"2020","unstructured":"Dom\u00ednguez Vivero C, Leira Y, Saavedra Pi\u00f1eiro M, Rodr\u00edguez-Osorio X, Ramos-Cabrer P, Villalba Mart\u00edn C et al (2020) Iron deposits in periaqueductal gray matter are associated with poor response to onabotulinumtoxinA in chronic migraine. Toxins (Basel). https:\/\/doi.org\/10.3390\/toxins12080479","journal-title":"Toxins (Basel)."},{"key":"2869_CR21","doi-asserted-by":"publisher","DOI":"10.1177\/17448069231178176","author":"X-X Fang","year":"2023","unstructured":"Fang X-X, Zhai M-N, Zhu M, He C, Wang H, Wang J et al (2023) Inflammation in pathogenesis of chronic pain: Foe and friend. Mol Pain. https:\/\/doi.org\/10.1177\/17448069231178176","journal-title":"Mol Pain"},{"key":"2869_CR22","unstructured":"FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016. http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK326791\/"},{"key":"2869_CR23","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","volume":"14","author":"NB Finnerup","year":"2015","unstructured":"Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH et al (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neur 14:162\u2013173. https:\/\/doi.org\/10.1016\/S1474-4422(14)70251-0","journal-title":"Lancet Neur"},{"key":"2869_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jpsychires.2013.11.006","volume":"52","author":"E Finzi","year":"2014","unstructured":"Finzi E, Rosenthal NE (2014) Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial. J Psychiatr Res 52:1\u20136. https:\/\/doi.org\/10.1016\/j.jpsychires.2013.11.006","journal-title":"J Psychiatr Res"},{"key":"2869_CR25","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1159\/000342125","volume":"25","author":"GG Gauglitz","year":"2012","unstructured":"Gauglitz GG, Bureik D, Dombrowski Y, Pavicic T, Ruzicka T, Schauber J (2012) Botulinum toxin A for the treatment of keloids. Skin Pharmacol Physiol 25:313\u2013318. https:\/\/doi.org\/10.1159\/000342125","journal-title":"Skin Pharmacol Physiol"},{"key":"2869_CR26","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.pain.2008.10.005","volume":"141","author":"P Gazerani","year":"2009","unstructured":"Gazerani P, Pedersen NS, Staahl C, Drewes AM, Arendt-Nielsen L (2009) Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin. Pain 141:60\u201369. https:\/\/doi.org\/10.1016\/j.pain.2008.10.005","journal-title":"Pain"},{"key":"2869_CR27","doi-asserted-by":"publisher","first-page":"2436","DOI":"10.1093\/brain\/awab461","volume":"145","author":"L Gfrerer","year":"2022","unstructured":"Gfrerer L, Xu W, Austen W, Ashina S, Melo-Carrillo A, Longhi MS et al (2022) OnabotulinumtoxinA alters inflammatory gene expression and immune cells in chronic headache patients. Brain 145:2436\u20132449. https:\/\/doi.org\/10.1093\/brain\/awab461","journal-title":"Brain"},{"key":"2869_CR28","doi-asserted-by":"publisher","first-page":"62","DOI":"10.3844\/crdsp.2021.62.70","volume":"12","author":"R Hajj","year":"2021","unstructured":"Hajj R, Haddad C (2021) The anti-nociceptive\/anti-inflammatory actions of botulinum toxin a for the treatment of chronic pain: a literature review. Current Res Dent 12:62\u201370. https:\/\/doi.org\/10.3844\/crdsp.2021.62.70","journal-title":"Current Res Dent"},{"key":"2869_CR29","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1111\/jocd.12534","volume":"17","author":"R Hao","year":"2018","unstructured":"Hao R, Li Z, Chen X, Ye W (2018) Efficacy and possible mechanisms of botulinum toxin type A on hypertrophic scarring. J Cosmet Dermatol [internet] 17:340\u2013346. https:\/\/doi.org\/10.1111\/jocd.12534","journal-title":"J Cosmet Dermatol [internet]"},{"key":"2869_CR30","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2016.00497","author":"CS Hubbard","year":"2016","unstructured":"Hubbard CS, Becerra L, Smith JH, DeLange JM, Smith RM, Black DF et al (2016) Brain changes in responders vs non-responders in chronic migraine: markers of disease reversal. Front Hum Neurosci. https:\/\/doi.org\/10.3389\/fnhum.2016.00497","journal-title":"Front Hum Neurosci"},{"key":"2869_CR1","unstructured":"Ines Novo Pereira, Sara Dur\u00e3o, Giancarlo De la Torre Canales, Ana Cristina Braga, Andr\u00e9 Mariz Almeida, Haidar Hassan, et al. Biomarkers in Preclinical Research on Botulinum Toxin effects on Inflammation-associated Chronic Conditions. PROSPERO 2023 CRD42023432411 [Internet]. https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD42023432411"},{"key":"2869_CR53","unstructured":"Ines Novo Pereira, Sara Dur\u00e3o, Haidar Hassan, Ana Cristina Braga, Andr\u00e9 Mariz Almeida, Ana Cristina Manso, et al. Biomarkers in clinical research on botulinum toxin effects on inflammation-associated chronic conditions. PROSPERO 2023 CRD2023432131 [Internet]. https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD42023432131"},{"key":"2869_CR31","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000001438","author":"HS Jeong","year":"2015","unstructured":"Jeong HS, Lee BH, Sung HM, Park SY, Ahn DK, Jung MS et al (2015) Effect of botulinum toxin type A on differentiation of fibroblasts derived from scar tissue. Plast Reconstr Surg. https:\/\/doi.org\/10.1097\/PRS.0000000000001438","journal-title":"Plast Reconstr Surg"},{"key":"2869_CR32","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1136\/jnnp-2017-316250","volume":"89","author":"R Kaji","year":"2018","unstructured":"Kaji R, Bhatia K, Graybiel AM (2018) Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? J Neurol Neurosurg Psychiatry 89:488\u2013492. https:\/\/doi.org\/10.1136\/jnnp-2017-316250","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2869_CR33","doi-asserted-by":"publisher","DOI":"10.17116\/jnevro201711712133-36","author":"YV Karakulova","year":"2017","unstructured":"Karakulova YV, Loginova NV (2017) The efficacy of botulinotherapy in the correction of the pain syndrome and quality of life of patients with cervical dystonia. Zh Nevrol Psikhiatr Im S S Korsakova. https:\/\/doi.org\/10.17116\/jnevro201711712133-36","journal-title":"Zh Nevrol Psikhiatr Im S S Korsakova"},{"key":"2869_CR34","doi-asserted-by":"publisher","DOI":"10.1111\/dth.15748","author":"BHM Khatery","year":"2022","unstructured":"Khatery BHM, Hussein HA, Abd-El-Raheem TA, El Hanbuli HM, Yassen NN (2022) Assessment of intralesional injection of botulinum toxin type A in hypertrophic scars and keloids: Clinical and pathological study. Dermatol Ther. https:\/\/doi.org\/10.1111\/dth.15748","journal-title":"Dermatol Ther"},{"key":"2869_CR35","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1097\/DSS.0000000000001819","volume":"45","author":"MJ Kim","year":"2019","unstructured":"Kim MJ, Kim JH, Cheon HI, Hur MS, Han SH, Lee YW et al (2019) Assessment of skin physiology change and safety after intradermal injections with botulinum toxin: a randomized, double-blind, placebo-controlled, split-face pilot study in rosacea patients with facial erythema. Dermatol Surg [internet] 45:1155\u20131162. https:\/\/doi.org\/10.1097\/DSS.0000000000001819","journal-title":"Dermatol Surg [internet]"},{"key":"2869_CR36","doi-asserted-by":"publisher","DOI":"10.3390\/toxins13050332","author":"H Kim","year":"2021","unstructured":"Kim H, Jang B, Kim S-T (2021) Botulinum Toxin Type-A (Botulax\u00ae) Treatment in Patients with Intractable Chronic Occipital Neuralgia: A Pilot Study. Toxins (Basel). https:\/\/doi.org\/10.3390\/toxins13050332","journal-title":"Toxins (Basel)."},{"key":"2869_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2016.01.054","author":"MJ Lee","year":"2016","unstructured":"Lee MJ, Lee C, Choi H, Chung C-S (2016) Factors associated with favorable outcome in botulinum toxin A treatment for chronic migraine: A clinic-based prospective study. J Neurol Sci. https:\/\/doi.org\/10.1016\/j.jns.2016.01.054","journal-title":"J Neurol Sci"},{"key":"2869_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-80283-4","author":"Y Leira","year":"2021","unstructured":"Leira Y, Dom\u00ednguez C, Ameijeira P, L\u00f3pez-Arias E, \u00c1vila-G\u00f3mez P, P\u00e9rez-Mato M et al (2021) Mild systemic inflammation enhances response to OnabotulinumtoxinA in chronic migraineurs. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-020-80283-4","journal-title":"Sci Rep"},{"key":"2869_CR39","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2021.584416","author":"Y Li","year":"2021","unstructured":"Li Y, Liu T, Luo W (2021) Botulinum neurotoxin therapy for depression: therapeutic mechanisms and future perspective. Front Psychiatry. https:\/\/doi.org\/10.3389\/fpsyt.2021.584416","journal-title":"Front Psychiatry."},{"key":"2869_CR40","doi-asserted-by":"publisher","DOI":"10.3390\/toxins13110751","author":"S Luvisetto","year":"2021","unstructured":"Luvisetto S (2021) Botulinum neurotoxins in central nervous system: an overview from animal models to human therapy. Toxins. https:\/\/doi.org\/10.3390\/toxins13110751","journal-title":"Toxins"},{"key":"2869_CR41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.805657","author":"JA Mapunda","year":"2022","unstructured":"Mapunda JA, Tibar H, Regragui W, Engelhardt B (2022) How does the immune system enter the brain? Front Immunol. https:\/\/doi.org\/10.3389\/fimmu.2022.805657","journal-title":"Front Immunol"},{"key":"2869_CR42","unstructured":"Marcolino MA. Independent implementation of the ROBINS-I assessment tool, with academic purposes, with no collaboration or revision from the developers of the tool itself. Also, no alterations on the content of the ROBINS-I tool or language was performed. [Internet]. https:\/\/www.iats.com.br\/uploads\/ROBINS-I-ExcelTool-unoficial_macro.xlsm"},{"key":"2869_CR43","doi-asserted-by":"publisher","first-page":"5001","DOI":"10.3390\/ijms24055001","volume":"24","author":"L Marek-Jozefowicz","year":"2023","unstructured":"Marek-Jozefowicz L, Nedoszytko B, Grochocka M, \u017bmijewski MA, Czajkowski R, Cuba\u0142a WJ et al (2023) Molecular mechanisms of neurogenic inflammation of the skin. Int J Mol Sci 24:5001. https:\/\/doi.org\/10.3390\/ijms24055001","journal-title":"Int J Mol Sci"},{"key":"2869_CR44","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00540-018-2579-4","volume":"33","author":"M Matsuda","year":"2019","unstructured":"Matsuda M, Huh Y, Ji R-R (2019) Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J Anesth 33:131\u2013139. https:\/\/doi.org\/10.1007\/s00540-018-2579-4","journal-title":"J Anesth"},{"key":"2869_CR45","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-019-0989-9","author":"R Moreno-Mayordomo","year":"2019","unstructured":"Moreno-Mayordomo R, Ruiz M, Pascual J, Gallego de la Sacristana M, Vidriales I, Sobrado M et al (2019) CALCA and TRPV1 genes polymorphisms are related to a good outcome in female chronic migraine patients treated with OnabotulinumtoxinA. J Headache Pain. https:\/\/doi.org\/10.1186\/s10194-019-0989-9","journal-title":"J Headache Pain"},{"key":"2869_CR46","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1136\/ebmed-2017-110668","volume":"22","author":"MH Murad","year":"2017","unstructured":"Murad MH, Mustafa RA, Sch\u00fcnemann HJ, Sultan S, Santesso N (2017) Rating the certainty in evidence in the absence of a single estimate of effect. Evid Based Med [internet] 22:85\u201387. https:\/\/doi.org\/10.1136\/ebmed-2017-110668","journal-title":"Evid Based Med [internet]"},{"key":"2869_CR49","unstructured":"OCEBM Levels of Evidence Working Group*. The Oxford Levels of Evidence 2 [Internet]. Oxford Centre for Evidence-Based Medicine. Available from: https:\/\/www.cebm.ox.ac.uk\/resources\/levels-of-evidence\/ocebm-levels-of-evidence* OCEBM Levels of Evidence Working Group = Jeremy Howick, Iain Chalmers (James Lind Library), Paul Glasziou, Trish Greenhalgh, Carl Heneghan, Alessandro Liberati, Ivan Moschetti, Bob Phillips, Hazel Thornton, Olive Goddard and Mary Hodgkinson"},{"key":"2869_CR50","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2022.107357","author":"M Ozarslan","year":"2022","unstructured":"Ozarslan M, Matur Z, Tuzun E, Oge AE (2022) Cutaneous allodynia and thermal thresholds in chronic migraine: The effect of onabotulinumtoxinA. Clin Neurol Neurosur. https:\/\/doi.org\/10.1016\/j.clineuro.2022.107357","journal-title":"Clin Neurol Neurosur"},{"key":"2869_CR51","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71","author":"MJ Page","year":"2020","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, The PRISMA et al (2020) statement: an updated guideline for reporting systematic reviews. BMJ. https:\/\/doi.org\/10.1136\/bmj.n71","journal-title":"BMJ"},{"key":"2869_CR52","doi-asserted-by":"publisher","DOI":"10.1007\/s00403-019-01975-0","author":"GS Park","year":"2019","unstructured":"Park GS, An MK, Yoon JH, Park SS, Koh SH, Mauro TM et al (2019) Botulinum toxin type A suppresses pro-fibrotic effects via the JNK signaling pathway in hypertrophic scar fibroblasts. Arch Dermatol Res. https:\/\/doi.org\/10.1007\/s00403-019-01975-0","journal-title":"Arch Dermatol Res"},{"key":"2869_CR54","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1002\/nau.24534","volume":"40","author":"ES Philippova","year":"2021","unstructured":"Philippova ES, Bazhenov IV, Ziryanov AV, Bazarny VV (2021) Impact of intradetrusor botulinum toxin A injections on serum and urinary concentrations of nerve growth factor and brain-derived neurotrophic factor in patients with multiple sclerosis and neurogenic detrusor overactivity. Neurourol Urodyn [internet] 40:95\u2013101. https:\/\/doi.org\/10.1002\/nau.24534","journal-title":"Neurourol Urodyn [internet]"},{"key":"2869_CR55","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1202341","author":"N Reyes","year":"2023","unstructured":"Reyes N, Huang JJ, Choudhury A, Pondelis N, Locatelli EV, Felix ER et al (2023) Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia. Front Neurosci. https:\/\/doi.org\/10.3389\/fnins.2023.1202341","journal-title":"Front Neurosci"},{"key":"2869_CR56","unstructured":"Ronya Sari, Noor Al-Huda Monemsdatter Hadi, Henrik Winther Schytz. Biomarker predictors of Botulinum Toxin A efficacy in chronic migraine patients. PROSPERO 2021 CRD42021265014 [Internet]. : https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD42021265014"},{"key":"2869_CR57","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.jclinepi.2023.05.010","volume":"159","author":"HJ Sch\u00fcnemann","year":"2023","unstructured":"Sch\u00fcnemann HJ, Brennan S, Akl EA, Hultcrantz M, Alonso-Coello P, Xia J et al (2023) The development methods of official GRADE articles and requirements for claiming the use of GRADE\u2013A statement by the GRADE guidance group. J Clin Epidemiol 159:79\u201384. https:\/\/doi.org\/10.1016\/j.jclinepi.2023.05.010","journal-title":"J Clin Epidemiol"},{"key":"2869_CR58","doi-asserted-by":"publisher","DOI":"10.3390\/toxins15010076","author":"G Sebastianelli","year":"2023","unstructured":"Sebastianelli G, Casillo F, Di Renzo A, Abagnale C, Cioffi E, Parisi V et al (2023x) Effects of botulinum toxin type A on the nociceptive and lemniscal somatosensory systems in chronic migraine: an electrophysiological study. Toxins (Basel). https:\/\/doi.org\/10.3390\/toxins15010076","journal-title":"Toxins (Basel)."},{"key":"2869_CR59","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.toxicon.2019.12.153","volume":"178","author":"X Shi","year":"2020","unstructured":"Shi X, Gao C, Wang L, Chu X, Shi Q, Yang H et al (2020) Botulinum toxin type A ameliorates adjuvant-arthritis pain by inhibiting microglial activation-mediated neuroinflammation and intracellular molecular signaling. Toxicon [internet] 178:33\u201340. https:\/\/doi.org\/10.1016\/j.toxicon.2019.12.153","journal-title":"Toxicon [internet]"},{"key":"2869_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2021.108523","author":"A Shoari","year":"2021","unstructured":"Shoari A, Kanavi MR, Rasaee MJ (2021) Inhibition of matrix metalloproteinase-9 for the treatment of dry eye syndrome; a review study. Exp Eye Res. https:\/\/doi.org\/10.1016\/j.exer.2021.108523","journal-title":"Exp Eye Res"},{"key":"2869_CR61","doi-asserted-by":"publisher","first-page":"1838","DOI":"10.1016\/j.jaad.2020.04.082","volume":"83","author":"U Shon","year":"2020","unstructured":"Shon U, Kim MH, Lee DY, Kim SH, Park BC (2020) The effect of intradermal botulinum toxin on androgenetic alopecia and its possible mechanism. J Am Acad Dermatol [internet] 83:1838\u20131839. https:\/\/doi.org\/10.1016\/j.jaad.2020.04.082","journal-title":"J Am Acad Dermatol [internet]"},{"key":"2869_CR62","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2017.02.429","author":"S Smith","year":"2017","unstructured":"Smith S, Dworkin R, Turk D, Baron R, Polydefkis M, Tracey I et al (2017) The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT Considerations. J Pain. https:\/\/doi.org\/10.1016\/j.jpain.2017.02.429","journal-title":"J Pain"},{"key":"2869_CR63","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i4919","author":"JA Sterne","year":"2016","unstructured":"Sterne JA, Hern\u00e1n MA, Reeves BC, Savovi\u0107 J, Berkman ND, Viswanathan M et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. https:\/\/doi.org\/10.1136\/bmj.i4919","journal-title":"BMJ"},{"key":"2869_CR64","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l4898","author":"JAC Sterne","year":"2019","unstructured":"Sterne JAC, Savovi\u0107 J, Page MJ, Elbers RG, Blencowe NS, Boutron I et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. https:\/\/doi.org\/10.1136\/bmj.l4898","journal-title":"BMJ"},{"key":"2869_CR65","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.14536","author":"T Todberg","year":"2018","unstructured":"Todberg T, Zachariae C, Bregnh\u00f8j A, Hedelund L, Bonefeld KK, Nielsen K et al (2018) The effect of botulinum neurotoxin A in patients with plaque psoriasis\u2013an exploratory trial. J Eur Acad Dermatol Venereol. https:\/\/doi.org\/10.1111\/jdv.14536","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"2869_CR66","doi-asserted-by":"publisher","DOI":"10.3390\/toxins13060392","author":"M Valente","year":"2021","unstructured":"Valente M, Lettieri C, Russo V, Janes F, Gigli GL (2021) Clinical and neurophysiological effects of botulinum neurotoxin type a in chronic migraine. Toxins. https:\/\/doi.org\/10.3390\/toxins13060392","journal-title":"Toxins"},{"key":"2869_CR67","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1007\/s00266-009-9423-z","volume":"34","author":"Z Xiao","year":"2010","unstructured":"Xiao Z, Zhang F, Lin W, Zhang M, Liu Y (2010) Effect of botulinum toxin type A on transforming growth factor beta1 in fibroblasts derived from hypertrophic scar: a preliminary report. Aesthetic Plast Surg [internet] 34:424\u2013427. https:\/\/doi.org\/10.1007\/s00266-009-9423-z","journal-title":"Aesthetic Plast Surg [internet]"},{"key":"2869_CR68","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1007\/s00266-011-9690-3","volume":"35","author":"Z Xiao","year":"2011","unstructured":"Xiao Z, Zhang M, Liu Y, Ren L (2011) Botulinum toxin type a inhibits connective tissue growth factor expression in fibroblasts derived from hypertrophic scar. Aesthetic Plast Surg [internet] 35:802\u2013807. https:\/\/doi.org\/10.1007\/s00266-011-9690-3","journal-title":"Aesthetic Plast Surg [internet]"},{"key":"2869_CR69","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1177\/1090820X13482938","volume":"34","author":"W Xiaoxue","year":"2014","unstructured":"Xiaoxue W, Xi C, Zhibo X (2014) Effects of botulinum toxin type A on expression of genes in keloid fibroblasts. Aesthet Surg J [internet] 34:154\u2013159. https:\/\/doi.org\/10.1177\/1090820X13482938","journal-title":"Aesthet Surg J [internet]"},{"key":"2869_CR70","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnaa028","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Lian Y, Zhang H, Xie N, Chen Y (2020) CGRP plasma levels decrease in classical trigeminal neuralgia patients treated with botulinum toxin type a: a pilot study. Pain Med. https:\/\/doi.org\/10.1093\/pm\/pnaa028","journal-title":"Pain Med"},{"key":"2869_CR71","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.820817","author":"S Zhang","year":"2022","unstructured":"Zhang S, Li K, Yu Z, Chai J, Zhang Z, Zhang Y et al (2022) Dramatic effect of botulinum toxin type A on hypertrophic scar: a promising therapeutic drug and its mechanism through the SP-NK1R pathway in cutaneous neurogenic inflammation. Front Med (Lausanne). https:\/\/doi.org\/10.3389\/fmed.2022.820817","journal-title":"Front Med (Lausanne)."},{"key":"2869_CR72","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.ejphar.2018.07.033","volume":"834","author":"X Zhuang","year":"2018","unstructured":"Zhuang X, Xu H, Fang Z, Xu C, Xue C, Hong X (2018) Platelet serotonin and serotonin transporter as peripheral surrogates in depression and anxiety patients. Eur J Pharmacol [internet] 834:213\u2013220. https:\/\/doi.org\/10.1016\/j.ejphar.2018.07.033","journal-title":"Eur J Pharmacol [internet]"}],"container-title":["Journal of Neural Transmission"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00702-024-02869-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00702-024-02869-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00702-024-02869-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:47:32Z","timestamp":1764600452000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00702-024-02869-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":72,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["2869"],"URL":"https:\/\/doi.org\/10.1007\/s00702-024-02869-w","relation":{},"ISSN":["0300-9564","1435-1463"],"issn-type":[{"type":"print","value":"0300-9564"},{"type":"electronic","value":"1435-1463"}],"subject":[],"published":{"date-parts":[[2025,3,4]]},"assertion":[{"value":"22 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests or personal relationships that could have influence this paper.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}