Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent

ABSTRACT

Introduction

Especially when acutely ill, individuals with schizophrenia and bipolar disorder can present with agitated behavior. The initial approach to agitation management are non-pharmacologic strategies such as verbal de-escalation techniques; however, pharmacologic interventions may be needed. Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist, and a sublingual formulation has been approved in the US for the treatment of agitation associated with schizophrenia and bipolar disorder in adults.

Areas covered

The authors review the published literature on sublingual dexmedetomidine using the US National Library of Medicine’s PubMed.gov resource. Pharmacodynamics, pharmacokinetics, and efficacy and tolerability findings are summarized. The authors also provide a discussion to its potential place in the treatment armamentarium.

Expert opinion

Sublingual dexmedetomidine is an effective and well-tolerated pharmacologic option for the treatment of agitation associated with schizophrenia and bipolar disorder. The sublingual method of administration allows for a rapid onset of action with treatment effects beginning as early as 20 minutes after administration. Adverse effects include somnolence, hypotension, oral paresthesia, hypoesthesia, and dry mouth. Further study will be needed to evaluate sublingual dexmedetomidine in real-world patients receiving concomitant psychotropic medications.

KEYWORDS:

• Schizophrenia
• bipolar disorder
• psychopharmacology
• sublingual
• agitation
• aggression
• dexmedetomidine
• pharmacodynamics
• pharmacokinetics

Article highlights

• Sublingual dexmedetomidine allows for the rapid, noninvasive treatment of agitation in patients with bipolar disorder or schizophrenia. It is the only approved sublingual medication for the treatment of agitation in patients with schizophrenia and bipolar disorder.

• Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist. The mechanism of action in the treatment of acute agitation is thought to be due to the activation of presynaptic alpha-2 adrenergic autoreceptors in the locus coeruleus, resulting in a decrease in release of central norepinephrine.

• Dexmedetomidine dosing as recommended in product labeling is based on severity of agitation, age, and absence or presence of hepatic impairment.

• Sublingual dexmedetomidine is absorbed in the oral mucosa, bypassing first-pass metabolism and achieving a higher bioavailability than if dexmedetomidine were to be ingested.

• In two Phase 3, randomized, double-blind, placebo-controlled trials in patients with schizophrenia or schizoaffective disorder and in patients with bipolar I or II disorder, patients receiving sublingual dexmedetomidine demonstrated statistically significant greater improvements in the Positive and Negative Syndrome Scale – Excited Component (PEC) total score than placebo as early as 20 min after drug administration.

• The most common adverse reactions of sublingual dexmedetomidine include somnolence, paresthesia, oral hypoesthesia, dizziness, hypotension, orthostatic hypotension, and dry mouth.

Declaration of Interest

J Faden is a consultant for BioXcel Therapeutics and Noven Pharmaceuticals. L Citrome is a consultant for: AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen Pharmaceuticals, Karuna, Lundbeck, Lyndra, Medavante-ProPhase, Marvin, Merck, Mitsubishi-Tanabe Pharma, Neurocrine, Neurelis, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sunovion, Supernus, Teva, and Vanda. Furthermore, he has served as speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva. L Citrome also holds stocks (small number of shares of common stock) from: Bristol-Myers Squibb, Eli Lilly and Company, Johnson & Johnson, Merck and Co and Pfizer Inc purchased >10 years ago and has stock options with: Reviva and receives royalties/publishing income from Taylor & Francis, Wiley, UpToDate, Springer Healthcare, and Elsevier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.