{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T22:48:05Z","timestamp":1788994085272,"version":"build-2803163510"},"reference-count":37,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R403-2022-1352"],"award-info":[{"award-number":["R403-2022-1352"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005111","name":"Rigshospitalet","doi-asserted-by":"publisher","award":["E-23831-03"],"award-info":[{"award-number":["E-23831-03"]}],"id":[{"id":"10.13039\/501100005111","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Cephalalgia"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Phosphodiesterase-5 (PDE-5) inhibition increases intracellular cyclic guanosine monophosphate (cGMP), a second messenger molecule implicated in migraine pathogenesis. Given the clinical overlap between migraine and post-traumatic headache (PTH), we investigated whether pharmacologic elevation of cGMP induces migraine-like headache in individuals with persistent PTH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adults with persistent PTH and no pre-trauma history of migraine were enrolled in a randomized, double-blind, placebo-controlled, 2-way crossover study. Each participant received a single 100-mg oral dose of sildenafil or placebo on two experimental days, separated by a 1-week washout interval. Headache outcomes were assessed using structured diaries over 12\u2005h post-ingestion. The primary outcome was the incidence of migraine-like headache during this observation window. The secondary outcome was the baseline-corrected area under the curve (AUC) for headache intensity scores over the same period.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 21 participants (mean age 42.3 years; 57% female) with persistent PTH completed both experimental days. Migraine-like headache occurred in 15 participants (71%) after sildenafil administration, compared with 4 (19%) following placebo (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20090.003). Headache intensity scores, as quantified by the AUC, were significantly higher after sildenafil than after placebo (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009&lt;\u20090.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Pharmacologic elevation of cGMP via PDE-5 inhibition elicits migraine-like headache in individuals with persistent PTH, despite no pre-trauma history of migraine. These findings provide the first experimental evidence linking intracellular cGMP-dependent signaling to headache provocation in this patient population. The observed response implicates cGMP-dependent mechanisms in the pathogenesis of PTH and identifies this pathway as a potential target for future therapeutic development.<\/jats:p>\n                    <jats:p>\n                      <jats:bold>Trial registration:<\/jats:bold>\n                      ClinicalTrials.gov (Identifier: NCT05669885).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/03331024261419409","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T11:34:14Z","timestamp":1773228854000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypersensitivity to phosphodiesterase-5 inhibition in post-traumatic headache: Evidence of cGMP-dependent signaling"],"prefix":"10.1177","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7015-3369","authenticated-orcid":false,"given":"Haidar M","family":"Al-Khazali","sequence":"first","affiliation":[{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3384-3579","authenticated-orcid":false,"given":"Rune H","family":"Christensen","sequence":"additional","affiliation":[{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna G","family":"Melchior","sequence":"additional","affiliation":[{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0951-5804","authenticated-orcid":false,"given":"Messoud","family":"Ashina","sequence":"additional","affiliation":[{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6268-727X","authenticated-orcid":false,"given":"H\u00e5kan","family":"Ashina","sequence":"additional","affiliation":[{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"},{"name":"Copenhagen University Hospital \u2013 Rigshospitalet"},{"name":"Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","unstructured":"Ashina H Eigenbrodt AK Seifert T et al. 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