Academic Journal
A randomized controlled clinical trial of intranasal versus subcutaneous midazolam for agitation in terminal illness (MinTU study).
| Title: | A randomized controlled clinical trial of intranasal versus subcutaneous midazolam for agitation in terminal illness (MinTU study). |
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| Authors: | Hirschinger H; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany.; Pharmacy, Mannheim University Hospital, Mannheim, Germany., Rémi C; Hospital Pharmacy and Department of Palliative Medicine, LMU University Hospital, LMU Munich, Munich, Germany., Jäger E; Institute for Clinical Chemistry, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Nittka S; Institute for Clinical Chemistry, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Hetjens S; Department of Medical Statistics, Biomathematics and Information Processing, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Saussele S; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Merx K; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Koch J; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Abba M; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Ghazal M; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Hofheinz RD; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Michaeli T; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Sperk E; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Kohlbrenner K; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Hofmann WK; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany., Gencer D; Oeschelbronn Clinic, Centre for Integrative Oncology, Pain and Palliative Medicine, Oeschelbronn, Germany., Boch T; 3rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany. |
| Source: | Palliative medicine [Palliat Med] 2026 Jun; Vol. 40 (6), pp. 856-867. Date of Electronic Publication: 2026 Mar 22. |
| Publication Type: | Journal Article; Randomized Controlled Trial; Clinical Trial, Phase II; Comparative Study |
| Language: | English |
| Journal Info: | Publisher: SAGE Publications Country of Publication: England NLM ID: 8704926 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-030X (Electronic) Linking ISSN: 02692163 NLM ISO Abbreviation: Palliat Med Subsets: MEDLINE |
| Imprint Name(s): | Publication: London : SAGE Publications Original Publication: London : New York, NY : Cambridge University Press, North American distributors, Edward Arnold ; c1987- |
| MeSH Terms: | Midazolam*/administration & dosage , Midazolam*/therapeutic use , Psychomotor Agitation*/drug therapy , Hypnotics and Sedatives*/administration & dosage , Palliative Care*/methods , Terminally Ill*/psychology , Terminal Care*/methods, Humans ; Female ; Administration, Intranasal ; Male ; Aged ; Injections, Subcutaneous ; Middle Aged ; Treatment Outcome ; Aged, 80 and over |
| Abstract: | Background: Terminally ill patients often have difficulty taking medications. Suitable, minimally invasive, fast-acting administration routes are particularly important. Trials on alternative drug administration routes in palliative care are essential to base therapy decisions on evidence rather than experience. Aim: To evaluate the effectiveness of intranasal compared with subcutaneous midazolam for the initial management of terminal agitation in palliative care patients. Design: Randomized, investigator-initiated open-label phase-II trial, August 2022-July 2024. Setting/participants: Monocentric trial at the palliative care ward of a German University Hospital. 180 patients were assessed for suitability, 60 patients (median age, 68 years (SD 12.3), 26 female) were randomized 1:1 and analyzed. Patients with terminal agitation fulfilling all eligibility criteria were randomized to midazolam 5 mg administered either intranasal (n = 30) or subcutaneous (n = 30). Primary Outcome: Improvement of terminal agitation by midazolam administration assessed by RASS-PAL-score. Secondary Outcome: Midazolam plasma concentrations after administration. Results: Median RASS-PAL-scores decreased significantly in both groups. Intranasal group: 2 at baseline, to -1 at 5 min and -2 at 20 min. Subcutaneous group: 1,-0 and -1. Within-group reductions exceeded the clinically relevant threshold of ⩾ 1 point at 5 and 20 min (all p < 0.0001). Median midazolam plasma concentrations were significantly higher intranasal (5 min: 90 ng/ml, 20 min: 83 ng/ml) than subcutaneous (5 min: 15 ng/ml, 20 min: 24 ng/ml). No patients withdrawn due to adverse effects. Conclusion: Midazolam intranasal administration was effective in reducing terminal agitation and achieves higher plasma concentrations compared to subcutaneous administration. It is an alternative route of application to improve end-of-life care for terminally ill patients. Trial Registration: MinTU Study 173-01, Eudra CT No.: 2021-004789-36, DRKS ID: 00026775 (07.07.2022, https://drks.de/search/de/trial/DRKS00026775). |
| Competing Interests: | Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. |
| Contributed Indexing: | Keywords: agitation; end-of-life; intranasal; midazolam; palliative care |
| Substance Nomenclature: | R60L0SM5BC (Midazolam) 0 (Hypnotics and Sedatives) |
| Entry Date(s): | Date Created: 20260323 Date Completed: 20260713 Latest Revision: 20260713 |
| Update Code: | 20260714 |
| PubMed Central ID: | PMC13221569 |
| DOI: | 10.1177/02692163261428947 |
| PMID: | 41866851 |
| Database: | MEDLINE |
| ISSN: | 1477-030X |
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| DOI: | 10.1177/02692163261428947 |