{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:58:18Z","timestamp":1775804298680,"version":"3.50.1"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shenzhen Science and Technology Program Project","award":["JCYJ20220818102206014"],"award-info":[{"award-number":["JCYJ20220818102206014"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Refractory chronic cluster headache (rCCH) is a severe form of trigeminal autonomic primary headache that often resists conventional pharmacological treatment, resulting in significant impairment in patients\u2019 quality of life. Identifying effective strategies to reduce attack frequency and shorten cluster periods remains a crucial clinical challenge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>Two cases of rCCH who had suffered from recurrent paroxysmal headaches for several decades were reported. Both had received multiple medications over the long term, with suboptimal response. Given that vasodilation is a key pathophysiological feature of rCCH, an extremely low dose norepinephrine was administered to two cases during acute phase of headache depending on the vasoconstrictive effect of norepinephrine. Their headaches were alleviated significantly through systematic and adjustable titration therapy of extremely low dose norepinephrine for 1\u20132\u202fweeks. Following treatment, improvements were observed across multiple headache-related scales, including Cluster Headache Impact Questionnaire, Migraine-Specific Quality of Life Questionnaire, Migraine Disability Assessment Questionnaire, Health-Related Quality of Life, Hamilton Rating Scale for Depression and Hamilton Anxiety Scale. After the acute phase, both patients received preventive medications. At one-year follow-up, both patients remained attack-free under regular preventive therapy, had returned to normal daily activities, and maintained baseline scores on headache-related scales.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The administration of norepinephrine in these two cases suggests that extremely low dose norepinephrine may be a potential adjunctive option for acute exacerbations in rCCH patients who are unresponsive to multiple medications. However, further studies are needed to confirm its efficacy and safety.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1800150","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:02:54Z","timestamp":1775800974000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Extremely low dose norepinephrine in treatment of refractory chronic cluster headache: two case reports and literature review"],"prefix":"10.3389","volume":"20","author":[{"given":"Rong","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rulin","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiawei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoshuang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaixun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danyu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enxiang","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.3390\/jcm14072160","article-title":"Cluster headache and migraine shared and unique insights: neurophysiological implications, neuroimaging, and biomarkers: a comprehensive review","volume":"14","author":"Bertotti","year":"2025","journal-title":"J. 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