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Updated: Jun 16, 2026
Intranasal Administration of CNS Therapeutics to Awake Mice
Published on: April 8, 2013
A randomized controlled clinical trial of intranasal versus subcutaneous midazolam for agitation in terminal illness
Hanna Hirschinger1,2, Constanze Rémi3, Evelyn Jäger4
13rd Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, University Medical Center Mannheim, Mannheim, Germany.
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 No patients withdrawn due to adverse effects.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).
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