{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:36:08Z","timestamp":1790289368023,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"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>Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action in migraine prevention. Given that its mechanism of action is quite different from that of the new monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) or its receptor, it is unlikely to be displaced to any major extent by them. Both will likely remain as important tools for patients with chronic migraine and the clinicians assisting them. New types of botulinum toxin selective for sensory pain neurons may well be discovered or produced by recombinant DNA techniques in the coming decade, and this may greatly enhance its therapeutic usefulness. This review summarizes the evolution of botulinum toxin use in headache management over the past several decades and its role in the preventive treatment of chronic migraine and other headache disorders.<\/jats:p>","DOI":"10.3390\/toxins12120803","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T21:21:49Z","timestamp":1608240109000},"page":"803","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Botulinum Toxin in the Treatment of Headache"],"prefix":"10.3390","volume":"12","author":[{"given":"Werner J.","family":"Becker","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences, Foothills Medical Centre, University of Calgary, 1403 29th St. NW, Calgary, AB T2N 2T9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ion, I., Renard, D., Le Floch, A., De Verdal, M., Bouly, S., Wacongne, A., Lozza, A., and Castelnovo, G. (2018). Monocentric Prospective Study into the Sustained Effect of Incobotulinumtoxin A (XEOMIN(\u00ae)) Botulinum Toxin in Chronic Refractory Migraine. Toxins (Basel), 10.","DOI":"10.3390\/toxins10060221"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/j.1526-4610.2012.02288.x","article-title":"Headache direction and aura predict migraine responsiveness to rimabotulinumtoxin B","volume":"53","author":"Grogan","year":"2013","journal-title":"Headache"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00702-015-1478-1","article-title":"Botulinum toxin drugs: Brief history and outlook","volume":"123","author":"Dressler","year":"2016","journal-title":"J. Neural. Transm. (Vienna)"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Fonfria, E., Maignel, J., Lezmi, S., Martin, V., Splevins, A., Shubber, S., Kalinichev, M., Foster, K., Picaut, P., and Krupp, J. (2018). The Expanding Therapeutic Utility of Botulinum Neurotoxins. Toxins (Basel), 10.","DOI":"10.3390\/toxins10050208"},{"key":"ref_5","unstructured":"(2018). Headache Classification Committee of the International Headache Society (IHS) the International Classification of Headache Disorders. Cephalalgia, 38, 1\u2013211."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s10194-018-0846-2","article-title":"Migraine is first cause of disability in under 50s: Will health politicians now take notice?","volume":"19","author":"Steiner","year":"2018","journal-title":"J. Headache Pain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"394","DOI":"10.5334\/tohm.321","article-title":"History of Botulinum Toxin Treatment in Movement Disorders","volume":"6","author":"Jabbari","year":"2016","journal-title":"Tremor Other Hyperkinet Mov. (N. Y.)"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/j.1526-4610.1994.hed3408458.x","article-title":"Tension headache: Botulinum toxin paralysis of temporal muscles","volume":"34","author":"Zwart","year":"1994","journal-title":"Headache"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1046\/j.1526-4610.1998.3805366.x","article-title":"Headache and facial pain responsive to botulinum toxin: An unusual presentation of blepharospasm","volume":"38","author":"Johnstone","year":"1998","journal-title":"Headache"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1046\/j.1526-4610.1998.3806468.x","article-title":"Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension","volume":"38","author":"Wheeler","year":"1998","journal-title":"Headache"},{"key":"ref_11","first-page":"183","article-title":"Treatment of tension-type headache with botulinum toxin: A pilot study","volume":"4","author":"Wieser","year":"1999","journal-title":"Eur. J. Med. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1046\/j.1526-4610.1999.3909662.x","article-title":"Improvement of tension-type headache when treating wrinkles with botulinum toxin A injections","volume":"39","author":"Carruthers","year":"1999","journal-title":"Headache"},{"key":"ref_13","unstructured":"(2000). Feed a cold, starve a fever, poison a headache. Harv. Health Lett., 7."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1067\/mhn.2000.110960","article-title":"Botulinum toxin type A (BOTOX) for treatment of migraine headaches: An open-label study","volume":"123","author":"Binder","year":"2000","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1046\/j.1526-4610.2000.00066.x","article-title":"Botulinum toxin type A as a migraine preventive treatment. For. the BOTOX Migraine Clinical Research Group","volume":"40","author":"Silberstein","year":"2000","journal-title":"Headache"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1067\/maj.2002.121958","article-title":"Clinical results of botulinum toxin type a treatment of migraine headache","volume":"22","author":"Silberstein","year":"2002","journal-title":"Aesthet. Surg. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1111\/j.1526-4610.2005.05066.x","article-title":"Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: A randomized, double-blind, placebo-controlled trial","volume":"45","author":"Mathew","year":"2005","journal-title":"Headache"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.4065\/80.9.1126","article-title":"Botulinum toxin type A for the prophylactic treatment of chronic daily headache: A randomized, double-blind, placebo-controlled trial","volume":"80","author":"Silberstein","year":"2005","journal-title":"Mayo. Clin. Proc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1177\/0333102410364676","article-title":"OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial","volume":"30","author":"Aurora","year":"2010","journal-title":"Cephalalgia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1177\/0333102410364677","article-title":"OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial","volume":"30","author":"Diener","year":"2010","journal-title":"Cephalalgia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1111\/j.1526-4610.2010.01678.x","article-title":"OnabotulinumtoxinA for treatment of chronic migraine: Pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program","volume":"50","author":"Dodick","year":"2010","journal-title":"Headache"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s10194-018-0953-0","article-title":"Effects of onabotulinumtoxinA treatment in chronic migraine patients with and without daily headache at baseline: Results from the COMPEL Study","volume":"20","author":"Young","year":"2019","journal-title":"J. Headache Pain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1111\/j.1526-4610.2006.00624.x","article-title":"Botulinum toxin type a prophylactic treatment of episodic migraine: A randomized, double-blind, placebo-controlled exploratory study","volume":"47","author":"Aurora","year":"2007","journal-title":"Headache"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1111\/head.13849","article-title":"Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review","volume":"60","author":"Burstein","year":"2020","journal-title":"Headache"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.nbd.2015.04.011","article-title":"Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents","volume":"79","author":"Ramachandran","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4519","DOI":"10.3390\/toxins7114519","article-title":"Current status and future directions of botulinum neurotoxins for targeting pain processing","volume":"7","author":"Pellett","year":"2015","journal-title":"Toxins (Basel)"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1177\/0333102416636843","article-title":"Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors\u2019 responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?","volume":"36","author":"Zhang","year":"2016","journal-title":"Cephalalgia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1111\/head.12371","article-title":"Innervation of rat and human dura mater and pericranial tissues in the parieto-temporal region by meningeal afferents","volume":"54","author":"Schueler","year":"2014","journal-title":"Headache"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1097\/j.pain.0000000000000119","article-title":"OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine","volume":"156","author":"Larrosa","year":"2015","journal-title":"Pain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1152\/physrev.00034.2015","article-title":"Pathophysiology of Migraine: A Disorder of Sensory Processing","volume":"97","author":"Goadsby","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/ana.22329","article-title":"Activation of central trigeminovascular neurons by cortical spreading depression","volume":"69","author":"Zhang","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/nm0202-136","article-title":"Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model","volume":"8","author":"Bolay","year":"2002","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1111\/head.13843","article-title":"Dual Therapy with Anti-CGRP Monoclonal Antibodies and Botulinum Toxin for Migraine Prevention: Is There a Rationale?","volume":"60","author":"Pellesi","year":"2020","journal-title":"Headache"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10587","DOI":"10.1523\/JNEUROSCI.2211-17.2017","article-title":"Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (A\u03b4) But Not. Unmyelinated (C) Meningeal Nociceptors","volume":"37","author":"Strassman","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41582-018-0003-1","article-title":"CGRP as the target of new migraine therapies\u2014Successful translation from bench to clinic","volume":"14","author":"Edvinsson","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1111\/j.1526-4610.2010.01766.x","article-title":"Method of injection of onabotulinumtoxinA for chronic migraine: A safe, well-tolerated, and effective treatment paradigm based on the PREEMPT clinical program","volume":"50","author":"Blumenfeld","year":"2010","journal-title":"Headache"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/head.13074","article-title":"Insights into the Functional Anatomy Behind the PREEMPT Injection Paradigm: Guidance on Achieving Optimal Outcomes","volume":"57","author":"Blumenfeld","year":"2017","journal-title":"Headache"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1111\/head.13996","article-title":"Response to \u201cModifications to the PREEMPT Protocol for OnabotulinumtoxinA Injections for Chronic Migraine in Clinical Practice\u201d","volume":"60","author":"Blumenfeld","year":"2020","journal-title":"Headache"},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1177\/0333102414561873","article-title":"Long-term experience with onabotulinumtoxinA in the treatment of chronic migraine: What happens after one year?","volume":"35","author":"Larrosa","year":"2015","journal-title":"Cephalalgia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1111\/head.13630","article-title":"Prognosis Following Discontinuation of OnabotulinumA Therapy in \u201cSuper-responding\u201d Chronic Migraine Patients","volume":"59","author":"Ching","year":"2019","journal-title":"Headache"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1212\/WNL.0000000000002560","article-title":"Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology","volume":"86","author":"Simpson","year":"2016","journal-title":"Neurology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s10194-018-0921-8","article-title":"Guideline on the use of onabotulinumtoxinA in chronic migraine: A consensus statement from the European Headache Federation","volume":"19","author":"Bendtsen","year":"2018","journal-title":"J. Headache Pain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1111\/j.1526-4610.2009.01566.x","article-title":"A double-blind comparison of onabotulinumtoxina (BOTOX) and topiramate (TOPAMAX) for the prophylactic treatment of chronic migraine: A pilot study","volume":"49","author":"Mathew","year":"2009","journal-title":"Headache"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1111\/head.13653","article-title":"FORWARD Study: Evaluating the Comparative Effectiveness of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults with Chronic Migraine","volume":"59","author":"Rothrock","year":"2019","journal-title":"Headache"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1111\/head.13918","article-title":"Access to Migraine Treatments in Ontario, Canada: A Review of the Ontario Drug Benefit Program","volume":"60","author":"Cape","year":"2020","journal-title":"Headache"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/head.13754","article-title":"A Randomized Trial to Evaluate OnabotulinumtoxinA for Prevention of Headaches in Adolescents with Chronic Migraine","volume":"60","author":"Winner","year":"2020","journal-title":"Headache"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S1474-4422(17)30083-2","article-title":"Safety and efficacy of erenumab for preventive treatment of chronic migraine: A randomised, double-blind, placebo-controlled phase 2 trial","volume":"16","author":"Tepper","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2211","DOI":"10.1212\/WNL.0000000000006640","article-title":"Galcanezumab in chronic migraine: The randomized, double-blind, placebo-controlled REGAIN study","volume":"91","author":"Detke","year":"2018","journal-title":"Neurology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1177\/0333102419854082","article-title":"Long-term safety and tolerability of erenumab: Three-plus year results from a five-year open-label extension study in episodic migraine","volume":"39","author":"Ashina","year":"2019","journal-title":"Cephalalgia"},{"key":"ref_51","first-page":"568","article-title":"Evidence of and experience with the use of onabotulinumtoxinA in trigeminal neuralgia and primary headaches other than chronic migraine","volume":"35","author":"Cuadrado","year":"2020","journal-title":"Neurologia"},{"key":"ref_52","first-page":"e2","article-title":"The Use of Botulinum Toxin A in the Management of Trigeminal Neuralgia: A Systematic Literature Review","volume":"11","author":"Rubis","year":"2020","journal-title":"J. Oral. Maxillofac. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/papr.12773","article-title":"Efficacy of Botulinum Toxin in Tension-Type Headaches: A Systematic Review of the Literature","volume":"19","author":"Freund","year":"2019","journal-title":"Pain Pract."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1155\/2010\/914358","article-title":"A research synthesis of therapeutic interventions for whiplash-associated disorder (WAD): Part 5\u2014Surgical and injection-based interventions for chronic WAD","volume":"15","author":"Teasell","year":"2010","journal-title":"Pain Res. Manag."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1177\/0333102411398402","article-title":"Onabotulinum toxin A treatment of cervicogenic headache: A randomised, double-blind, placebo-controlled crossover study","volume":"31","author":"Linde","year":"2011","journal-title":"Cephalalgia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s11916-016-0570-z","article-title":"Interventional Treatment for Post-traumatic Headache","volume":"20","author":"Conidi","year":"2016","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1468-1331.2010.03056.x","article-title":"On muscle spindles, dystonia and botulinum toxin","volume":"17","author":"Rosales","year":"2010","journal-title":"Eur. J. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/s41415-019-0257-z","article-title":"A systematic review of botulinum toxin in the management of patients with temporomandibular disorders and bruxism","volume":"226","author":"Patel","year":"2019","journal-title":"Br. Dent. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.bjoms.2020.02.007","article-title":"Botulinum toxin in the management of temporomandibular disorders: A systematic review","volume":"58","author":"Thambar","year":"2020","journal-title":"Br. J. Oral. Maxillofac. Surg."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s00784-017-2092-4","article-title":"Is there enough evidence to use botulinum toxin injections for bruxism management? A systematic literature review","volume":"21","author":"Garcia","year":"2017","journal-title":"Clin. Oral. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fonfria, E., Elliott, M., Beard, M., Chaddock, J.A., and Krupp, J. (2018). Engineering Botulinum Toxins to Improve and Expand Targeting and SNARE Cleavage Activity. Toxins (Basel), 10.","DOI":"10.3390\/toxins10070278"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Armanious, M., Khalil, N., Lu, Y., and Jimenez-Sanders, R. (2020). Erenumab and OnabotulinumtoxinA Combination Therapy for the Prevention of Intractable Chronic Migraine without Aura: A Retrospective Analysis. J. Pain Palliat. Care Pharmacother., 1\u20136.","DOI":"10.1080\/15360288.2020.1829249"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/12\/803\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:46:12Z","timestamp":1760179572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/12\/803"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,17]]},"references-count":62,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["toxins12120803"],"URL":"https:\/\/doi.org\/10.3390\/toxins12120803","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,17]]}}}