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A new treatment for agitation in the emergency department or your inpatient unit? Here’s a randomized trial of a new oral treatment option. It’s company sponsored, but reassuringly the company had no access to the trial results until after the study was completed. On the other hand, some of the authors work for the company, and that’s not reassuring. Well, the drug is still worth learning about, so keep your skeptics glasses on and let’s have a look.
Hi! Jim Phelps here for the Psychopharmacology Institute. I suspect that nearly everyone in our profession has had enough experience with acutely agitated patients that you need no convincing. The more tools we have to cope with aggressive, angry, overenergized patients, the better everyone will be, especially if something new is convincingly lower in overall risk. If not, it better look extremely effective compared with current approaches to justify unknown longer-term risks and its likely high costs. So, what do we have here? That’s dexmedetomidine, an alpha-2 adrenergic receptor agonist that’s been around since 1999 as an intravenous drug used for sedation of intubated patients in intensive care.
Now, a pharmaceutical company has come up with a way to deliver dexmedetomidine sublingually using a dissolvable film. They just published a randomized trial in patients with a diagnosis of schizophrenia following an earlier study in patients with a diagnosis of bipolar disorder. Well, you know, we could save some time here. Published articles like this are just about guaranteed to show that the company drug is better than a placebo, so let’s just jump to the adverse effects table. If a new drug has hardly any more adverse effects than placebo, then maybe it’s worth checking it out further. Then we’ll go back and look at efficacy. Well, the main adverse effect of dexmedetomidine is somnolence, experienced by 20%–25% of patients vs 5%–8% of patients on placebo. The other notable problem was hypotension, 5%–6% of patients on dexmedetomidine vs zero on placebo.
Still interested? All right then. How much better was dexmedetomidine compared with placebo? In this study, the primary outcome measure was a subset of items from the Positive and Negative Syndrome Scale (PANSS), which has been used in schizophrenia research for decades. Twenty minutes after oral administration, the placebo agitation score had dropped 2.5 points vs 4 points on dexmedetomidine. On this subscale, that 1.5-point difference is statistically significant. But is it clinically significant? The authors say, “There is no consensus on the change in this score that represents the minimal clinically important difference.” But we don’t have to speculate because the authors offer another outcome measure, the Clinical Global Improvement Scale, which relies on subjective ratings of change from observers. On that scale, there was no observable difference between the groups at 30 minutes. It took until an hour after administration for patients on dexmedetomidine to be judged as being less agitated than patients on placebo, according to a supplementary table.
Before we wrap up then, parenthetically, here’s a nice trick. In these papers about dexmedetomidine, the company-associated authors listed adverse effects by frequency in the first paper and alphabetically in the second publication so that somnolence switched from the top of the list to the bottom. Nice trick.
In summary then, dexmedetomidine was not dramatically better than a placebo for rapid oral management of agitation. For a bigger picture, look at current treatment options. A team of emergency physicians wrote an excellent article that’s linked here at the Psychopharmacology Institute.
Abstract
Objective: Determine if sublingual dexmedetomidine, a selective α2 adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder.
Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 μg, 120 μg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose.
Results: Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African American) were randomized; 380 (100%) self-administered study medication, and 372 (97.9%) completed the study. The mean PEC total score at baseline (17.6) indicated mild to moderate agitation. At 2 hours postdose, the least squares mean changes (SE) from baseline were -10.3 (0.4) for sublingual dexmedetomidine 180 μg, -8.5 (0.4) for 120 μg, and -4.8 (0.4) for placebo. Least squares mean differences (97.5% confidence intervals) in the sublingual dexmedetomidine groups were -5.5 (-6.7 to -4.3) for 180 μg and -3.7 (-4.9 to -2.5) for 120 μg (both P < .001 vs placebo). The most commonly encountered adverse events with dexmedetomidine (incidence ≥ 5% and ≥ 2× rate observed with placebo) were somnolence, dry mouth, and hypotension for the 120 μg dose, and somnolence, dizziness, orthostatic hypotension, and oral hypoesthesia for the 180 μg dose.
Conclusions: Treatment with sublingual dexmedetomidine 180 μg or 120 μg was more efficacious than placebo in reducing acute agitation associated with schizophrenia as measured by PEC scores at 2 hours postdose.
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Reference
Citrome, L., Preskorn, S. H., Lauriello, J., Krystal, J. H., Kakar, R., Finman, J., De Vivo, M., Yocca, F. D., Risinger, R., & Rajachandran, L. (2022). Sublingual dexmedetomidine for the treatment of acute agitation in adults with schizophrenia or schizoaffective disorder: a randomized placebo-controlled trial. The Journal of Clinical Psychiatry, 83(6), 43180.
Related References
Treatment of Agitation (2021). University of Cincinnati. https://www.tamingthesru.com/blog/diagnostics/agitation
