Clinical Outcomes in Patients Taking Inhaled Loxapine, Haloperidol, or Ziprasidone in the Emergency Department.

OBJECTIVES: Our objective was to compare outcomes of discharge disposition, need for additional medications, and restraint use for patients who received inhaled loxapine compared with patients receiving traditional antipsychotic drugs in the emergency department (ED). METHODS: A retrospective chart review was conducted on all patients who presented to the ED with agitation and received antipsychotic therapy, including loxapine, ziprasidone, or haloperidol from December 1, 2014, through October 31, 2016. RESULTS: The mean time from physician assignment to medical clearance was 7.9 hours for patients treated with inhaled loxapine versus 10.3 hours for controls (P < 0.01). Those who received inhaled loxapine were given significantly less benzodiazepines as additional rescue medications as compared with other antipsychotic medications (P < 0.01, 35.2% vs 65.1%). Additionally, restraints were utilized less frequently in the loxapine group (P < 0.01, 1.8% vs 19.8%). CONCLUSIONS: Treating patients with agitation due to psychotic episodes in an ED setting with inhaled loxapine versus haloperidol or ziprasidone was associated with significantly improved treatment outcomes, suggesting that inhaled loxapine may be a more effective and rapid treatment option.

Inhaled Loxapine for the Management of Acute Agitation in Bipolar Disorder and Schizophrenia: Expert Review and Commentary in an Era of Change.

Agitation is a common and costly phenomenon associated with a number of psychiatric conditions including schizophrenia and bipolar disorder. Early identification and prompt intervention to relieve the symptoms of agitation are essential to avoid symptomatic escalation and emergence of aggressive behaviour. Recent consensus guidelines emphasise the need for non-coercive management strategies to protect the therapeutic alliance between patients and their healthcare providers-an alliance that is critical for the effective management of chronic psychiatric conditions. Rapid symptom relief and de-escalation of agitation are necessary to avoid the costly and traumatic use of coercive techniques of physical restraint and seclusion, which require admission and prolonged hospitalisation. Inhaled loxapine is approved for the treatment of acute agitation in patients with schizophrenia or bipolar disorder. Clinical studies have confirmed the efficacy, rapid onset of action, and safety and tolerability of this agent in the psychiatric emergency and hospital settings. Emerging data have indicated the potential for inhaled loxapine as a self-administered agent for use in the community setting without the direct supervision of a healthcare professional. We discuss the evolving treatment paradigm and the place of inhaled medications for acutely agitated patients both within and outside the emergency and hospital setting.

Inhaled loxapine for agitation in patients with personality disorder: an initial approach.

Inhaled Loxapine (IL) has demonstrated efficacy in the treatment of agitation in schizophrenic and bipolar patients, although data in patients with Personality Disorder (PD) are scarce. To evaluate the effectiveness and safety of IL in the treatment of agitation in PD, data from 41 patients who presented at our unit with acute agitation and were treated with 9.1 mg of IL were collected retrospectively. The results showed that IL significantly decreased agitation within 10 minutes and its effect was greater at 20 minutes (Positive and Negative Syndrome Scale-excited component: from 22.78 ±â€¯4.39 at baseline to 11.14 ±â€¯4.17 at 20 minutes; p < 0.001; Agitation and Calmness Evaluation Scale: from 1.80 ±â€¯0.49 at baseline to 4.53 ±â€¯1.05 at 20 minutes; p < 0.01) without any severe adverse reactions registered. IL led to fast, safe and well-tolerated control of agitation in patients with PD.

Safety and efficacy of self-administered inhaled loxapine (ADASUVE) in agitated patients outside the hospital setting: protocol for a phase IV, single-arm, open-label trial.

INTRODUCTION: There is a need for fast-acting, non-injection antiagitation treatments that are well tolerated and can be used outside of healthcare facilities. In phase II/III trials, an inhaled formulation of loxapine (ADASUVE®), a well-established, first-generation antipsychotic agent, provided rapid control of mild to moderate agitation in the hospital setting. The present study was designed to investigate the safety and efficacy of inhaled loxapine when self-administered outside the hospital setting. METHODS AND ANALYSIS: This phase IV, multicentre, single-arm, open-label clinical trial is being conducted in five countries in Europe: Spain, Germany, Norway, Romania and Austria. The aim is to include approximately 500 patients with schizophrenia or bipolar disorder who previously received and responded well to inhaled loxapine in the hospital setting. Eligible patients will be followed up for 6 months from baseline. They will be given a 10 mg dose of inhaled loxapine to self-administer outside the hospital setting to treat an agitation episode, should one occur. Patients will also be given a short-acting beta-agonist bronchodilator for treatment of possible severe respiratory side effects. The primary endpoint is incidence of serious adverse events (AEs) and respiratory AEs of special interest related to use of inhaled loxapine outside the hospital setting. Secondary endpoints include incidence of other AEs, Clinical Global Impression-Improvement scores up to 2 hours after self-administration of inhaled loxapine, time to improvement of agitation, patient satisfaction with treatment, treatment outcomes according to agitation severity and concordance between the patient (or a family member/caregiver) and the physician in scoring of agitation severity and the decision to self-administer inhaled loxapine. ETHICS AND DISSEMINATION: The protocol received ethics committee approval in the participating countries between January and August 2016. The results of this study will be disseminated through one or more scientific papers. TRIAL REGISTRATION NUMBER: EudraCT2015-003331-36; NCT02525991; Pre-results.

PLACID study: A randomized trial comparing the efficacy and safety of inhaled loxapine versus intramuscular aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder.

The aim of the study was to investigate the efficacy and safety of inhaled loxapine compared with the intramuscular (IM) antipsychotic aripiprazole in acutely agitated patients with schizophrenia or bipolar I disorder. PLACID was an assessor-blind, parallel-group trial conducted in 23 centres in the Czech Republic, Germany, Spain, and Russia. Patients (aged 18-65 years) diagnosed with schizophrenia or bipolar I disorder experiencing acute agitation (Clinical Global Impression [CGI]-Severity score ≥ 4) while hospitalized or attending an emergency room were randomized to receive up to two doses of inhaled loxapine 9.1 mg or IM aripiprazole 9.75 mg (≥ 2 h between doses) during the 24-h study period. The primary efficacy endpoint was time to response (CGI-Improvement score 1 [very much improved] or 2 [much improved]). The primary analysis included randomized patients who provided informed consent (full analysis set [FAS]); the safety analysis included all patients who received study medication. The FAS comprised 357 patients (enrolled December 2, 2014 - October 31, 2016). The between-treatment difference in median time to CGI-Improvement response was 10 min (95% CI 0.0-30.0); p = 0.0005) in favour of inhaled loxapine (median [95% CI]: 50 min [30.0-50.0] vs 60 min [50.0-90.0] with IM aripiprazole); the difference was significant at 10 min (responders: 14% [loxapine] vs 4% [aripiprazole]; p = 0.001). There were no safety issues. Inhaled loxapine reduced agitation faster than IM aripiprazole, supporting its use as a first-line option for managing acute agitation in patients with schizophrenia or bipolar disorder.

Inhaled Loxapine for Agitation in Intoxicated Patients: A Case Series.

OBJECTIVES: Episodes of agitation are frequent in intoxicated patients who have a substance use disorder, a psychiatric disorder or both (dual diagnosis). For managing the agitation, it is necessary to act promptly in a safe environment and addressing any underlying etiology. Inhaled loxapine improves symptoms of agitation in adults with psychiatric disorders (eg, schizophrenia) within 10 minutes of administration. Recently, some reports have documented the usefulness of loxapine in dual diagnoses patients with agitation. However, the efficacy of loxapine in intoxicated patients has not been deeply addressed. METHODS: This report describes a case series of 12 patients (with addiction or dual disorder) who received inhaled loxapine for symptoms of psychomotor agitation during intoxication with different substances (eg, alcohol, cannabis, or cocaine) at 1 center in Spain. RESULTS: Data from 12 patients were reviewed, 5 patients were attended at the emergency room, 4 at the addiction and dual diagnosis unit, and 3 were treated during hospitalization for detoxification. All patients were under effects of substances. They had substance use disorder (including cannabis, cocaine, alcohol, hypnotics, and hallucinogens), and almost all (90%) presented 1 or more psychiatric disorders. One dose of inhaled loxapine was effective in 9 patients (75%), and in 3 patients, a second dose was required. Only mild dizziness was reported in 1 patient after the second dose. CONCLUSIONS: The acute agitation was effectively and quickly managed with inhaled loxapine in all intoxicated patients and enabled the appropriate clinical evaluation of the agitated state and the patient's management.

[New medical approach to out-of-hospital treatment of psychomotor agitation in psychiatric patients: a report of 14 cases]. / Nuevo abordaje farmacológico en la agitación psicomotriz en pacientes psiquiátricos tratados en el medio extrahospitalario. A propósito de 14 casos.

OBJECTIVES: This case series explored the usefulness of an inhaled dose of 9.1 mg of loxapine administered outside the hospital to treat psychomotor agitation related to schizophrenia, bipolar disorder, or schizoaffective disorder. The Clinical Global Impression Scale and the Positive and Negative Syndrome Scale (excitement component) were used to assess the effects of treatment in 14 patients. The treatment was useful in 12 patients, who showed significant improvement (P<.001) after inhalation. We conclude that inhaled loxapine is useful for treating out-of-hospital psychomotor agitation related to a psychiatric disorder. Mechanical restraint and parenteral medication can be avoided after use of this drug. Loxapine treatment shortens the agitation episode and attenuates the impact on the patient, facilitating ambulance transfer.

OBJETIVO: El presente artículo evalúa la utilidad de la dosis de 9,1 mg de loxapina inhalada, administrada en el medio extrahospitalario, en el tratamiento de la agitación psicomotriz asociada a esquizofrenia, trastorno bipolar y trastorno esquizoafectivo. Se emplearon la Escala de Impresión Clínica Global y la Escala de Síntomas Positivos y Negativos - Componente de Excitación. Se atendieron un total de catorce pacientes. En doce de ellos el tratamiento se mostró útil, con una diferencia significativa entre los momentos previos y posteriores al tratamiento (p < 0,001). Se concluye que la loxapina inhalada es una opción útil en el medio extrahospitalario para el control de la agitación psicomotriz de causa psiquiátrica. Evita la contención mecánica y la necesidad de terapia farmacológica por vía parenteral. El tratamiento permite acortar la duración del episodio y atenuar su repercusión en el paciente, sin producir sedación y facilitando su traslado en ambulancia.

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation.

We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management.

Nuevo abordaje farmacológico en la agitación psicomotriz en pacientes psiquiátricos tratados en el medio extrahospitalario. A propósito de 14 casos / New medical approach to out-of-hospital treatment of psychomotor agitation in psychiatric patients: a report of 14 cases

El presente artículo evalúa la utilidad de la dosis de 9,1 mg de loxapina inhalada, administrada en el medio extrahospitalario, en el tratamiento de la agitación psicomotriz asociada a esquizofrenia, trastorno bipolar y trastorno esquizoafectivo. Se emplearon la Escala de Impresión Clínica Global y la Escala de Síntomas Positivos y Negativos - Componente de Excitación. Se atendieron un total de catorce pacientes. En doce de ellos el tratamiento se mostró útil, con una diferencia significativa entre los momentos previos y posteriores al tratamiento (p < 0,001). Se concluye que la loxapina inhalada es una opción útil en el medio extrahospitalario para el control de la agitación psicomotriz de causa psiquiátrica. Evita la contención mecánica y la necesidad de terapia farmacológica por vía parenteral. El tratamiento permite acortar la duración del episodio y atenuar su repercusión en el paciente, sin producir sedación y facilitando su traslado en ambulancia (AU)

This case series explored the usefulness of an inhaled dose of 9.1 mg of loxapine administered outside the hospital to treat psychomotor agitation related to schizophrenia, bipolar disorder, or schizoaffective disorder. The Clinical Global Impression Scale and the Positive and Negative Syndrome Scale (excitement component) were used to assess the effects of treatment in 14 patients. The treatment was useful in 12 patients, who showed significant improvement (P<.001) after inhalation. We conclude that inhaled loxapine is useful for treating out-of-hospital psychomotor agitation related to a psychiatric disorder. Mechanical restraint and parenteral medication can be avoided after use of this drug. Loxapine treatment shortens the agitation episode and attenuates the impact on the patient, facilitating ambulance transfer (AU)

Pharmacist intervention to detect drug adverse events on admission to the emergency department: Two case reports of neuroleptic malignant syndrome.

WHAT IS KNOWN AND OBJECTIVE: Neuroleptic malignant syndrome (NMS) is a rare but severe adverse effect of antipsychotic drugs. CASE DESCRIPTION: We report two cases of NMS highlighted by clinical pharmacists in an emergency unit during summer. One of them was fatal. Medication reconciliation processes performed at admission identified treatment with loxapine for one of them and with loxapine and clozapine for the other. Interview of the patients highlighted clinical symptoms suggesting NMS, allowing the pharmacists to alert the medical team. WHAT IS NEW AND CONCLUSION: Adverse drug events may be severe and clinical pharmacists in emergency departments can help to detect them.

Rationale and design of the PLACID study: a randomised trial comparing the efficacy and safety of inhaled loxapine versus IM aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder.

BACKGROUND: The management of acute agitation manifesting in patients with schizophrenia or bipolar disorder requires swift pharmacological intervention to provide rapid symptomatic relief and prevent escalation to aggression and violence. Antipsychotic medications are widely used in this setting and the availability of an inhaled formulation with deep lung absorption of the antipsychotic loxapine has the potential to deliver a faster onset of therapeutic effect than the available intramuscular formulations of antipsychotics. METHODS: The efficacy of inhaled loxapine and the alternative antipsychotic aripiprazole delivered via intramuscular (IM) injection will be compared in the Phase IIIb PLACID study. Adults (18-65 years) with a confirmed diagnosis of schizophrenia or bipolar I disorder presenting with acute agitation will be randomly assigned to open-label treatment in a 1:1 ratio. Clinical evaluation will be conducted by raters blinded to treatment assignment. The primary efficacy endpoint is time to response (defined as a Clinical Global Impression of Improvement [CGI-I] score of 1 [very much improved] or 2 [much improved]). Secondary endpoints will include the percentage of responders at different time points after dosing; the proportion of patients who receive 1 or 2 doses of study drug; time to second dose; time to rescue medication; satisfaction with study drug (evaluated using Item 14 of the Treatment Satisfaction Questionnaire for Medication); and safety and tolerability. Approximately 360 patients will be recruited with an interim analysis conducted once 180 patients have completed the study to decide whether to stop for futility or continue with or without an increase in the sample size up to additional 288 patients. DISCUSSION: The PLACID trial will assess the efficacy and safety of inhaled loxapine with deep lung absorption compared with the IM antipsychotic, aripiprazole, in acutely agitated patients with schizophrenia or bipolar disorder. In the event that the median time to response of inhaled loxapine is significantly shorter than that of the intramuscular aripiprazole, the PLACID study has the potential to support the inhaled antipsychotic therapy as the standard of care in this setting. TRIAL REGISTRATION: The study protocol was registered with the European Clinical Trials Database on the 31 October 2014 (EudraCT number 2014-000456-29 ).

The Role of Inhaled Loxapine in the Treatment of Acute Agitation in Patients with Psychiatric Disorders: A Clinical Review.

Loxapine is a first generation antipsychotic, belonging to the dibenzoxazepine class. Recently, loxapine has been reformulated at a lower dose, producing an inhaled powder that can be directly administered to the lungs to treat the agitation associated with psychiatric disorders, such as schizophrenia and bipolar disorder. Thus, the aim of this narrative and clinical mini-review was to evaluate the efficacy and tolerability of inhaled loxapine in the treatment of acute agitation in patients with psychiatric disorders. The efficacy of inhaled loxapine has been evaluated in one Phase II trial on patients with schizophrenia, and in two Phase III trials in patients with schizophrenia and bipolar disorder. Moreover, there are two published case series on patients with borderline personality disorder and dual diagnosis patients. Inhaled loxapine has proven to be effective and generally well tolerated when administered to agitated patients with schizophrenia and bipolar disorder. Two case series have suggested that inhaled loxapine may also be useful to treat agitation in patients with borderline personality disorder and with dual diagnosis, but further studies are needed to clarify this point. However, the administration of inhaled loxapine requires at least some kind of patient collaboration, and is not recommended in the treatment of severe agitation in totally uncooperative patients. Moreover, the drug-related risk of bronchospasm must always be kept in mind when planning to use inhaled loxapine, leading to a careful patient assessment prior to, and after, administration. Also, the higher costs of inhaled loxapine, when compared to oral and intramuscular medications, should be taken into account when selecting it for the treatment of agitation.

Clinical Trial Simulations and Pharmacometric Analysis in Pediatrics: Application to Inhaled Loxapine in Children and Adolescents.

BACKGROUND AND OBJECTIVES: Loxapine for inhalation is a drug-device combination product approved in adults for the acute treatment of agitation associated with schizophrenia or bipolar I disorder. The primary objective of this study was to develop a clinical trial protocol to support a phase I pharmacokinetic study in children aged 10 years and older. In addition, this report details the results of the clinical study in relation to the predicted likelihood of achieving the target exposure associated with therapeutic effect in adults. METHODS: A nonlinear mixed-effects population pharmacokinetic model was developed using adult data and was adjusted for the targeted pediatric age groups by applying allometric scaling to account for body size effects. Based on this pediatric model, age-appropriate regimens to achieve loxapine exposures similar to the ones associated with therapeutic effect in the adult studies were identified via trial simulation. D-optimal design and power analysis were conducted to identify optimal pharmacokinetic sampling times and sample size, respectively. RESULTS: The developed clinical trial design formed the basis of a phase I study to assess the safety and pharmacokinetics of loxapine for inhalation in children aged 10 years and older (ClinicalTrials.gov ID: NCT02184767). CONCLUSION: The results of the study indicated that overall loxapine exposures were consistent with what had been predicted by the trial simulations. The presented approach illustrates how modeling and simulation can assist in the design of informative clinical trials to identify safe and effective doses and dose ranges in children and adolescents.

The effect of the medicine administration route on health-related quality of life: Results from a time trade-off survey in patients with bipolar disorder or schizophrenia in 2 Nordic countries.

BACKGROUND: Agitation episodes are common among patients with schizophrenia or bipolar disorder. Oral and intramuscular administration methods are commonly used in pharmacological treatment of acute agitation. Recently, an innovative inhalation product with loxapine(Adasuve®)has become available for treatment of acute agitation episodes associated with bipolar disorder or schizophrenia. The objective for the present study was to investigate the impact of the pharmacological treatment's administration methods on the health-related quality of life (HRQoL) in patients with bipolar disorder or schizophrenia in Denmark and Sweden using a time trade-off (TTO) approach. METHODS: The TTO methodology was used to examine the HRQoL impact of administration method of pharmacological treatment of acute agitation. Data were collected via an internet-based survey, using an existing panel of respondents with schizophrenia or bipolar disorder. RESULTS: Respondents considered living with schizophrenia/ bipolar disorder, having one yearly agitation episode treated with inhaler better than living with the same conditions and receiving treatment with tablet or injection. The utility value was 0.762 for inhalable treatment, 0.707 for injection and 0.734 for tablet treatment. CONCLUSIONS: Patients' preference for treatment delivery options showed that inhalation was associated with a significant utility gain when compared to injection or tablets. Inhalable loxapine may be a new tool for control of agitation episodes for strengthening the patient provider alliance when taking patient's preference for delivery method into consideration.

Inhaled drug therapy development for the treatment of migraine.

INTRODUCTION: The inhalation of substances, both medicinally and recreationally, is a commonly used method of drug administration but has been underutilized in the treatment of neurologic disorders such as migraine. Three drugs have been studied as potential inhalable treatments for acute migraine: dihydroergotamine (MAP0004), prochlorperazine (Staccato prochlorperazine), and loxapine (Staccato loxapine). AREAS COVERED: This review discusses the available literature describing the pharmacokinetics, tolerability and efficacy of MAP0004, Staccato prochlorperazine and Staccato loxapine, including data from Phase II and Phase III clinical trials. EXPERT OPINION: Inhaled DHE offers rapid absorption with a pharmacokinetic profile similar to IV administration. Improved side effect profile results from more selective binding at antimigraine serotonergic receptors 5-HT1B and 5-HT1D. Inhaled prochlorperazine is rapidly absorbed and resulted in statistically significant migraine pain relief at 2 hours compared to placebo but is not currently being pursued by the manufacturer as a potential migraine abortive. Inhaled loxapine is also rapidly absorbed into systemic circulation but Phase IIb trials did not show statistically improved pain relief or pain freedom compared to placebo. MAP0004 will likely provide a good alternative to patients seeking rapid relief without the need for injection or other invasive routes.

Inhaled loxapine for the urgent treatment of acute agitation associated with schizophrenia or bipolar disorder.

BACKGROUND: Acute agitation is a serious complication of schizophrenia and bipolar disorder, which may escalate quickly to aggressive behavior. Rapid treatment is therefore important to calm and stabilize the patient, reducing the potential for harm to the patient and others, and allowing further assessment. Current guidelines suggest that where pharmacologic intervention is indicated, medication should preferably be non-invasive, should have a rapid onset and should control aggressive behavior in the short term without compromising the physician-patient relationship in the long term. OBJECTIVES: This article presents an overview of a new inhaled formulation of the established antipsychotic loxapine, which aims to provide a more rapidly acting agent for the treatment of acute agitation without the disadvantages of intramuscular or intravenous injection. DISCUSSION: Inhaled loxapine is rapidly absorbed with intravenous-like pharmacokinetics, with a time to maximum plasma concentration of 2 minutes and a plasma half-life of approximately 6 hours. In phase III studies, loxapine reduced agitation within 10 minutes of inhalation; agitation was decreased at all subsequent assessments during a 24-hour evaluation period. Inhaled loxapine was generally well tolerated with no undue sedation. The most common adverse events were dysgeusia, mild sedation, and dizziness. Inhaled loxapine is contraindicated in patients with asthma, COPD or other pulmonary disease associated with bronchospasm. CONCLUSIONS: Inhaled loxapine rapidly reduces acute agitation in patients with schizophrenia or bipolar disorder and is generally well tolerated. The non-invasive route of delivery respects the patient's autonomy, reducing the perception of coercion or forced medication. Inhaled loxapine is therefore an effective and appropriate option for use in the emergency setting in patients with acute agitation.

Managing Agitation Associated with Schizophrenia and Bipolar Disorder in the Emergency Setting.

INTRODUCTION: Patient agitation represents a significant challenge in the emergency department (ED), a setting in which medical staff are working under pressure dealing with a diverse range of medical emergencies. The potential for escalation into aggressive behavior, putting patients, staff, and others at risk, makes it imperative to address agitated behavior rapidly and efficiently. Time constraints and limited access to specialist psychiatric support have in the past led to the strategy of "restrain and sedate," which was believed to represent the optimal approach; however, it is increasingly recognized that more patient-centered approaches result in improved outcomes. The objective of this review is to raise awareness of best practices for the management of agitation in the ED and to consider the role of new pharmacologic interventions in this setting. DISCUSSION: The Best practices in Evaluation and Treatment of Agitation (BETA) guidelines address the complete management of agitation, including triage, diagnosis, interpersonal calming skills, and medicine choices. Since their publication in 2012, there have been further developments in pharmacologic approaches for dealing with agitation, including both new agents and new modes of delivery, which increase the options available for both patients and physicians. Newer modes of delivery that could be useful in rapidly managing agitation include inhaled, buccal/sublingual and intranasal formulations. To date, the only formulation administered via a non-intramuscular route with a specific indication for agitation associated with bipolar or schizophrenia is inhaled loxapine. Non-invasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and healthcare providers. CONCLUSION: Management of agitation in the ED should encompass a patient-centered approach, incorporating non-pharmacologic approaches if feasible. Where pharmacologic intervention is necessary, a cooperative approach using non-invasive medications should be employed where possible.