{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:08:07Z","timestamp":1789708087293,"version":"4.0.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Nocebo effects, driven by negative expectations rather than pharmacological mechanisms, are an under-recognized cause of adverse effects in clinical practice. Although experimental studies have used expectation manipulation to explore these phenomena, translation into clinical diagnostic approaches remains limited. We report the first clinical application of a novel provocation protocol in a single patient as an n-of-1 trial to illustrate its potential to identify whether reported adverse events in this patient were driven by nocebo mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed an extension of the crossover balanced placebo design incorporating additional manipulation of patient expectations comprising five structured provocation sessions using an active substance or placebo combined with correct, and intentionally misleading declarations under open-label and blinded conditions. As a proof-of-concept this protocol was applied to a single patient with self-reported alcohol intolerance using ethanol and water. Symptom severity for each provocation was assessed using a numeric rating scale and analyzed descriptively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The most severe symptoms followed the administration of open-label ethanol (mean numeric rating scale [NRS] 5.3; maximum 8) and water deceptively labeled as ethanol (mean NRS 4.1; maximum 7), while blinded ethanol (mean NRS 2.8; maximum 5) and blinded water (mean NRS 2.6, maximum 5) produced only mild reactions. These findings are consistent with adverse reactions in this single patient primarily driven by expectations, indicating a nocebo mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This report demonstrates the proof-of-concept value of a novel \u201cmixed open blinded crossover balanced placebo provocation protocol\u201d and illustrates the potential to identify nocebo effects in clinical practice. Whether this exploratory finding have broader relevance warrants investigation in larger cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1913605","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:37:29Z","timestamp":1789706249000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel provocation protocol to identify nocebo effects in clinical practice\u2014a proof-of-concept n-of-1 study"],"prefix":"10.3389","volume":"17","author":[{"given":"Martin","family":"Coenen","sequence":"first","affiliation":[{"name":"Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunther","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"B\u00fcttner","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn","place":["Bonn, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-74904-9","volume-title":"Alcohol Metabolism, Alcohol Intolerance, and Alcoholism","author":"Agarwal","year":"1990"},{"key":"B2","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1111\/all.15996","article-title":"EAACI\/ENDA position paper on drug provocation testing","volume":"79","author":"Barbaud","year":"2024","journal-title":"Allergy Eur. 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