Sublingual dexmedetomidine: An old drug with a new route for agitation

Abstract

Sublingual dexmedetomidine under the tradename of IgalmiTM is the first and only FDA-approved sedative agent for treating agitation in schizophrenia and bipolar I or II patients. This article highlights the benefits and adverse effects associated with this novel route of administration of dexmedetomidine and its potential to emerge as a promising sedative agent.

Agitation is a prevalent and challenging symptom that affects approximately 42%–71% of critically ill patients in the intensive care unit (ICU).[1] Acute agitation is a medical emergency that poses a threat not only to the patient but also to the surrounding personnel. It leads to considerable morbidity, increased length of ICU stay, and a significant burden on the patient and the healthcare system. Acute agitation is associated with motor and verbal restlessness, hyperactivity, hyperarousability, and irritability.[2] Thus, early identification and management of agitation are urgently needed to counter worsening symptoms that progress to aggression.

A wide armamentarium of drugs has been tried to counter agitation in critically ill patients in the ICU, the first-line being antipsychotics and/or benzodiazepines, such as midazolam, lorazepam, haloperidol, and aripiprazole. Various other agents, including dexmedetomidine, propofol, and fentanyl, have also been used for ICU sedation.

An ideal anti-agitation drug should have a safe profile and fast onset, calm down the patient without causing oversedation or decreased consciousness, and have a noninvasive route of administration. Dexmedetomidine has been used mainly via the intravenous (IV) route for ICU sedation. In this article, we will discuss the latest noninvasive route of administration approved for dexmedetomidine.

What is Already Known About Dexmedetomidine in the ICU?

Dexmedetomidine is a highly selective alpha-2 (α-2) adrenoceptor agonist, which was U.S. Food and Drug Administration (FDA)-approved in 1999 for analgesia and ICU sedation.[3] It is well-known for causing sedation, hypnosis, sympatholysis, analgesia, and anxiolysis along with minimal respiratory depression. It is nearly 94% bound to plasma protein and crosses the blood-brain and placental barriers. The activation of presynaptic α-2 autoreceptors in locus coeruleus leads to a decline in norepinephrine release, which in turn causes a decline in sympathetic activity, thus causing anti-agitation.

The adverse effects of dexmedetomidine are drowsiness, sleepiness, paraesthesia around the oral cavity, light-headedness, xerostomia, hypotension, and orthostatic hypotension, which are generally mild to moderate in intensity.

The bioavailability of dexmedetomidine is variable, depending on the route of administration, which has been found to be 16% with the oral route, 72% after sublingual administration, and even higher with buccal dosing (82%).[2]

The metabolism of dexmedetomidine is primarily by the liver, through direct glucuronidation by uridine 5’-dishosphoglucuronosyltransferase and CYP450-mediated oxidation. This breaks it down into inactive metabolites that are largely excreted in urine (95%) and stool (4%).

Novel Route of Dexmedetomidine Administration

Agitation has been found to be a key symptom in 13% of individuals with bipolar illness and 21% of patients with schizophrenia.[4] Sedatives have been administered by various methods, including inhalation, intramuscular, IV, and oral, to counter agitation in the ICU. The most popular route, oral, offers the benefits of being noninvasive and easy to administer but is associated with a slow onset of action and variable absorption profile.

Sublingual use of dexmedetomidine, under the trade name of IGALMI™, is the first and only FDA-approved drug used to treat acute agitation in 2022 in adult patients with schizophrenia or bipolar I or II disorder.[5] Two phase-III clinical trials that were double-masked and placebo-controlled and randomly assigned to 758 patients evaluated it. The action of sublingual dexmedetomidine was observed to start as early as 20 minutes. It is currently available in two forms: 120 and 180-microgram films, which are made with two dots and can be split into two to have half of the original strength. This mucoadhesive film bypasses the first-pass metabolism by being immediately absorbed into the oral mucosa and takes as short as 6–8 minutes to dissolve completely. It has been shown to carry a lower risk of psychological and physical stress to the patients. Another added advantage of sublingual dexmedetomidine is the absence of extrapyramidal effects by not acting on the dopamine receptor, which prevents the stigma attached to using antipsychotics.[4]

The arsenal of undesirable effects among the 180-mcg group, sublingual dexmedetomidine was associated with somnolence (23%), oral paraesthesia (7%), hypotension, dizziness (6%), hypotension or orthostatic hypotension (5%), dry mouth (4%), nausea (3%), and bradycardia (2%).[2] All these adverse effects are more profound in hypotensive, geriatric, hypovolemic, chronic hypertensive, and diabetic patients. A dose-dependent impact of prolonged QT interval of 6–8 ms from baseline is also observed with it.

Patients are advised to be kept nil per oral for a duration of 15 minutes following the sublingual dexmedetomidine administration.

Khan et al. conducted a randomized, double-blinded control study in children aged 2–12 years to compare the plasma concentration of intranasal and sublingual dexmedetomidine. They found that the intranasal at a dose of 2 mcg/kg has a relatively high and rapid plasma concentration (P = 0.001), but both have comparable sedative profiles.[6]

Although it has been used in various studies [Table 1],[6,7,8,9,10,11,12,13] the efficacy and safety profile of sublingual dexmedetomidine has not yet been determined beyond 24 hours after the administration of the primary dose. Its use is restricted in cases of hypotension and cardiac conditions, including heart blocks, arrhythmias, torsades de pointes, and severe ventricular dysfunction. Metabolic derangements, including hypokalemia and hypomagnesemia, can also limit its use. Patients are advised not to drive, operate machinery, or perform any physical action requiring mental focus for at least 8 hours after its administration.

Table 1.

Sublingual dexmedetomidine: An old drug with a new route

Author, Year Country	Study Design	Age (in years)	Number of patients/participants	Outcomes	Results	Conclusion
Mohamed et al.,[7] 2021 Egypt	Prospective, randomized double-blind comparative study	30–60	36	Does formulating the drug as a gel decrease oral losses and improve the absorption of buccal dexmedetomidine applied for sedative premedication in 3 dose cohorts (0.5, 0.75, and 1 µg/kg) in women undergoing modified radical mastectomy?	Median time to reach maximal concentration was significantly shorter in the 1 µg/kg group with no significant differences between groups in other pharmacokinetic parameters.	Sublingual dexmedetomidine formulated as an oral-mucosal gel may provide a safe and practical means of sedative premedication in adults.
Preskorn et al.,[8] 2022 Finland	Randomized, double-blind, placebo-controlled study	18–75	459	To evaluate the effect of orally absorbed sublingual dexmedetomidine on symptoms of acute agitation in patients with bipolar disorder.	Among patients with mild to moderate agitation associated with bipolar disorder, treatment with an investigational sublingual film formulation of dexmedetomidine 180 µg or 120 µg, compared with placebo, resulted in a significantly greater reduction in the agitation score at 2 hours.	Decrease in the agitation score.
Yanik et al.,[9] 2023 Turkey	Retrospective RCT	39–72	59	To investigate transmucosal dexmedetomidine used with local anesthesia during fiberoptic bronchoscopy (FOB). Other: comparison of sublingual vs. intranasal groups for success rate, safety, and applicability.	Sedation scores for groups at 1st, 9th, 12th, and 15th min were similar. Patients in both groups had no complaints of swallowing, excessive body movement, or lower oxygen saturation during examination (P>0.05).	The sublingual and intranasal groups had similar characteristics in terms of achieving adequate sedation levels, high patient and operator satisfaction, and low complication rates.
Shaat et al.,[10] 2021 Egypt	Randomized controlled clinical trial with a crossover design	5-7	42	To test the hypothesis that there is no difference between intranasal and sublingual routes of administration of dexmedetomidine on: acceptance of the child regarding the drug administration route, time to reach the desired level of sedation, child’s anxiety level reached during local anesthesia administration, and postoperative effects of sedation.	The sublingual dexmedetomidine route was better accepted than the intranasal route (P=0.01), while the latter acted faster (P>0.001). No significant difference in anxiety scores between groups at baseline or during local anesthetic (LA) administration. No negative effect was recorded by the parents, 24 hours after the dental visit compared to before the dental visit.	Both routes prevented the increase in anxiety scores equally during LA and did not have a negative effect on the postoperative behavior of children. The sublingual route showed better acceptance with a longer onset time of action than the intranasal route.
Khan et al.,[6] 2025 India	Randomized, double-blind	2-12	40	Primary: to compare peak plasma concentration, time to reach peak plasma concentration, and area under the curve with 2 µg/kg sublingual and intranasal dexmedetomidine premedication in children. Secondary aim: to compare the depth of sedation, parental separation anxiety, mask acceptance, heart rate changes, analgesic requirement and recovery time.	2 µg/kg intranasal dexmedetomidine resulted in significantly higher and faster median peak concentration in comparison to the sublingual route.	Intranasal 2 µg/kg dexmedetomidine resulted in a significantly higher peak plasma concentration and a shorter time to reach peak plasma concentration than sublingual wafers. Both groups resulted in comparable sedation, parental separation anxiety, and mask acceptance without significant bradycardia.
Schnider et al.,[11] 2025 Switzerland	Randomized, placebo-controlled, balanced, double-blind, crossover design	18-35	25	To examine the feasibility of oromucosal and sublingual dexmedetomidine administration.	In poor sleepers, 40 µg buccal dexmedetomidine shortened the sleep latency by 11.5 min, increased the time spent in non-rapid eye movement (NREM) sleep by 37.2 min, and elevated NREM sleep electroencephalographic slow-wave energy (0.75 to 4.0 Hz) in the first half of the night by roughly 23%.	The favorable pharmacokinetic and pharmacodynamic profile of oromucosal dexmedetomidine delivery warrants further dose-finding and clinical studies to establish the exact roles of α2 receptor agonism in pharmacologic sleep enhancement and as a possible novel mechanism to alleviate stress-related insomnia.
Pant et al.,[12] 2014 India	Prospective, randomized, double-blind study	1-12	100	Evaluated the effectiveness of sublingual dexmedetomidine for premedication in children and compare it with sublingual midazolam. The primary endpoint was sedation upon parental separation and behavior at time of anesthesia induction. The secondary endpoint was mask acceptance at the time of anesthesia induction, behavior at the time of wake-up from anesthesia, and hemodynamic changes.	The median sedation score at parental separation was 6 in the midazolam group as compared to 3.5 in the dexmedetomidine group. The median mask acceptance score and wake-up behavior score) in preschool children was 2 in the midazolam group as compared to 1 in the dexmedetomidine group.	Sublingual dexmedetomidine provides more effective preoperative sedation as compared to sublingual midazolam across all age groups and allows a smooth anesthesia induction and awakening, especially in the pre- school children.
Jones et al.,[13] 2023 USA	Randomized, double-blind, placebo-controlled trial	18-65	225	Assessed the safety of sublingual dexmedetomidine (BXCL501) and its preliminary efficacy in treating opioid withdrawal.	Higher doses of dexmedetomidine led to hypotension, orthostatic hypotension, and somnolence.	The safety, tolerability, and preliminary efficacy observed in the current trial support the further development of BXCL501 (sublingual dexmedetomidine) in the treatment of opioid withdrawal.

Sublingual dexmedetomidine is the latest FDA-approved drug and is safe and efficient, has a rapid onset, requires almost no need for repeated dosing, and has remarkable sedative properties in schizophrenic and bipolar patients. It is associated with minimal adverse consequences, thus avoiding extrapyramidal symptoms, leading to better drug compliance. A relatively lower dose is recommended for elderly and hepatic impairment patients.

Considering the potential benefits of sublingual dexmedetomidine, it can emerge as a novel alternative to sedative agents in critically ill patients on mechanical ventilation in the ICU, though its use is limited to schizophrenia and bipolar patients as of now. Further clinical trials are needed to establish its safety and efficacy in pregnant as well as lactating females.

Declaration of patient consent

All authors accept and confirm publication.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.