{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T12:32:53Z","timestamp":1777984373304,"version":"3.51.4"},"update-to":[{"DOI":"10.12688\/f1000research.164241.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000}}],"reference-count":36,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Norwegian National Program for Clinical Therapy Research, KLINBEFORSK","award":["[18\/00015-5]"],"award-info":[{"award-number":["[18\/00015-5]"]}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Background Treatment-resistant chronic migraine patients constitute a heavily burdened patient population with need for novel treatment options. The sphenopalatine ganglion (SPG), located deep within the facial structures, is a synaptic junction in the trigemino-autonomic reflex that is hypothesised to play a part in migraine pathophysiology. A 2017 open-label pilot study explored the SPG as a target for onabotulinumtoxinA injections in chronic migraine using a navigation-guided injection device, demonstrating a favourable safety profile and promising response on migraine related efficacy outcomes. Methods MiBlock is a multi-centre, investigator-initiated, publicly funded, randomised, quadruple-blinded and placebo-controlled trial. Participation is voluntary and all participants must sign a written consent prior to inclusion. The study is approved by the Norwegian ethics committee and the Norwegian Medical Product Agency. Patients with treatment-resistant chronic migraine will be recruited from four Norwegian university hospitals until 170 have received study treatment. The study will investigate the efficacy of a single-session, bilateral, navigation-guided, percutaneous injection of either onabotulinumtoxinA (verum) or 0.9% NaCl (placebo) towards the SPG under local anaesthesia. The primary efficacy endpoint is the change from baseline in the frequency of moderate and severe headache days at weeks 5-8 post-injection. The primary efficacy outcome variable is collected prospectively through daily headache eDiary entries during the entire study participation. The treatment effect will be assessed by comparing the placebo and the treatment arm according to a prespecified statistical analysis plan. Discussion This trial addresses a novel treatment strategy in headache prevention. The study is designed to evaluate the efficacy and safety of onabotulinumtoxinA injection towards the SPG in chronic migraine, but results may shed light on the feasibility of navigation-guided SPG injections in several headache disorders. Results will be published in international open-access peer-reviewed journals. Trial registration number EudraCT number: 2018-004053-24. ClinicalTrial ref: NCT04069897. 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Headache Pain."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"599-609","DOI":"10.1111\/j.1468-2982.2009.01941.x","article-title":"Global prevalence of chronic migraine: A systematic review.","volume":"30","author":"J Natoli","year":"2010","journal-title":"Cephalalgia."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"238-275","DOI":"10.1111\/head.13379","article-title":"History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From Translational Research to Treatment.","volume":"58 Suppl 3","author":"S Tepper","year":"2018","journal-title":"Headache."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"4-16","DOI":"10.1111\/head.13300","article-title":"A Phase-by-Phase Review of Migraine Pathophysiology.","volume":"58 Suppl 1","author":"D Dodick","year":"2018","journal-title":"Headache."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"115-127","DOI":"10.1097\/00004647-199902000-00001","article-title":"The trigeminovascular system in humans: Pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation.","volume":"19","author":"A May","year":"1999","journal-title":"J. Cerebr. Blood F. Met."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"438-442","DOI":"10.1097\/WCO.0000000000000691","article-title":"The unique role of the trigeminal autonomic reflex and its modulation in primary headache disorders.","volume":"32","author":"M Moller","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s10194-016-0664-3","article-title":"Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets.","volume":"17","author":"A Steinberg","year":"2016","journal-title":"J. Headache Pain."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"124-146","DOI":"10.1016\/j.tox.2013.02.006","article-title":"Botulinum toxins: mechanisms of action, antinociception and clinical applications.","volume":"306","author":"A Wheeler","year":"2013","journal-title":"Toxicology."},{"key":"ref11","article-title":"The anatomical and clinical relations of the sphenopalatine (Meckel\u2019s) ganglion to the nose and its accessory sinuses1909.","author":"G Sluder","year":"1909"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/s10194-017-0826-y","article-title":"Sphenopalatine ganglion: block, radiofrequency ablation and neurostimulation - a systematic review.","volume":"18","author":"K Ho","year":"2017","journal-title":"J. Headache Pain."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"816-830","DOI":"10.1177\/0333102412473667","article-title":"Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: A randomized, sham-controlled study.","volume":"33","author":"J Schoenen","year":"2013","journal-title":"Cephalalgia."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1081-1090","DOI":"10.1016\/S1474-4422(19)30322-9","article-title":"Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: A double-blind, randomised controlled trial.","volume":"18","author":"P Goadsby","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"101-116","DOI":"10.1111\/head.12458","article-title":"A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with tx360((R)) as acute treatment for chronic migraine.","volume":"55","author":"R Cady","year":"2015","journal-title":"Headache."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"529-542","DOI":"10.1111\/head.12546","article-title":"Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine.","volume":"55","author":"R Cady","year":"2015","journal-title":"Headache."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s10194-018-0843-5","article-title":"Measurement and implications of the distance between the sphenopalatine ganglion and nasal mucosa: A neuroimaging study.","volume":"19","author":"J Crespi","year":"2018","journal-title":"J. Headache Pain."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"356-364","DOI":"10.1177\/0333102416648328","article-title":"Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic migraine.","volume":"37","author":"D Bratbak","year":"2017","journal-title":"Cephalalgia."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"3331024241273967","DOI":"10.1177\/03331024241273967","article-title":"Open label experience of repeated OnabotulinumtoxinA injections towards the sphenopalatine ganglion in patients with chronic cluster headache and chronic migraine.","volume":"44","author":"L Simmonds","year":"2024","journal-title":"Cephalalgia."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"815-832","DOI":"10.1177\/0333102418758283","article-title":"Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine in adults.","volume":"38","author":"C Tassorelli","year":"2018","journal-title":"Cephalalgia."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"503-509","DOI":"10.1177\/0333102415597891","article-title":"Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic cluster headache.","volume":"36","author":"D Bratbak","year":"2016","journal-title":"Cephalalgia."},{"key":"ref22","article-title":"NOTE FOR GUIDANCE ON CLINICAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING (CPMP\/ICH\/377\/95).","year":"1995"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"396-397","DOI":"10.1016\/S1474-4422(18)30085-1","article-title":"International Classification of Headache Disorders.","volume":"17","author":"J Olesen","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s10194-020-01130-5","article-title":"European headache federation consensus on the definition of resistant and refractory migraine: Developed with the endorsement of the European Migraine & Headache Alliance (EMHA).","volume":"21","author":"S Sacco","year":"2020","journal-title":"J. Headache Pain."},{"key":"ref25","article-title":"Recommendations related to contraception and pregnancy testing in clinical trials Version 1.2.","year":"2024"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"963-974","DOI":"10.1023\/a:1026119331193","article-title":"A six-item short-form survey for measuring headache impact: the HIT-6.","volume":"12","author":"M Kosinski","year":"2003","journal-title":"Qual. Life Res."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"204-216","DOI":"10.1046\/j.1526-4610.2000.00030.x","article-title":"Validity and reliability of the migraine-specific quality of life questionnaire (MSQ Version 2.1).","volume":"40","author":"B Martin","year":"2000","journal-title":"Headache."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"353-365","DOI":"10.2165\/00019053-199304050-00006","article-title":"The validity and reproducibility of a work productivity and activity impairment instrument.","volume":"4","author":"M Reilly","year":"1993","journal-title":"PharmacoEconomics."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"361-370","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","article-title":"The hospital anxiety and depression scale.","volume":"67","author":"A Zigmond","year":"1983","journal-title":"Acta Psychiatr. Scand."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"117","DOI":"10.4103\/2229-3485.100663","article-title":"Protocol deviation and violation.","volume":"3","author":"A Bhatt","year":"2012","journal-title":"Perspect. Clin. Res."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"143-156","DOI":"10.1016\/j.cct.2003.10.016","article-title":"Assessment of blinding in clinical trials.","volume":"25","author":"H Bang","year":"2004","journal-title":"Control Clin. Trials."},{"key":"ref37","first-page":"1421-1434","article-title":"An index for assessing blindness in a multicenter clinical trial: disulfiram for alcohol cessation\u2014a VA cooperative study.","volume":"15","author":"K James","year":"1990","journal-title":"Stat. Med."},{"key":"ref32","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.28930940.v1","article-title":"Table 1, Eligibility criteria for participation in the MiBlock trial.","author":"T Wergeland","year":"2025","journal-title":"figshare. 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The funding body had no role in in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}