Ketamine for the Treatment for Alcohol Use Disorder in the ED

Study Overview
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Brief Summary
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The investigators' approach is to conduct a pilot double-blind, placebo-controlled randomized clinical trial with individuals with alcohol use disorder (AUD) seeking inpatient alcohol detoxification in the emergency department (ED) to receive either intravenous ketamine or saline placebo. The primary aim is to evaluate the intervention's safety. The secondary aim is to evaluate the preliminary efficacy of alcohol-related outcomes.

Detailed Description
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This is a pilot double-blind, placebo-controlled randomized clinical trial of 50 individuals with alcohol use disorder (AUD) presenting to the emergency department (ED) seeking inpatient detoxification to receive either a single infusion of ketamine 0.8mg/kg (n=25) or saline placebo (n=25). The study will be conducted at Brigham and Women's Faulkner Hospital (BWF), an urban, 171-bed hospital located in Boston, MA, and a major teaching hospital for Harvard Medical School (HMS). Participants will be randomized in a double-blind fashion to receive either ketamine or saline placebo in the ED. All participants will receive the institution's standard treatment, which includes detoxification, intensive psychosocial support, and referral to outpatient treatment. The intervention (ketamine) will consist of a single infusion of ketamine in the ED at a dose of 0.8mg/kg over 40 minutes, and the placebo will be a 0.9% saline solution also administered over 40 minutes. To determine the safety of administering ketamine the investigators will measure the incidence of severe adverse events (AE), defined as either hypertensive urgency (systolic blood pressure>180mmHg or diastolic blood pressure>110mmHg) or tachycardia (heart rate>130bpm). The investigators will also assess side effects, alcohol withdrawal, and craving for alcohol and ketamine. To determine the preliminary efficacy of ketamine on alcohol-related outcomes, the investigators will measure the proportion of abstinent days during the follow-up assessed using Timeline Follow-Back (TLFB). The investigators will also measure days to relapse, the proportion of heavy drinking days, engagement with addiction treatment, urine ketamine, and alcohol biomarkers (urine ethylglucuronide and serum phosphatidylethanol) at 28-days. The investigators hypothesize that results will show adequate safety and that those receiving ketamine, compared to placebo, will not experience more side effects, worse withdrawal, or greater alcohol or ketamine craving. The investigators also hypothesize that those receiving ketamine will report better drinking outcomes compared to placebo.

Official Title
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Ketamine for the Treatment for Alcohol Use Disorder in the Emergency Department: A Pilot Double-blind, Placebo-controlled Randomized Clinical Trial

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Drug: Ketamine
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: English speaking adults aged 18 and above Diagnosed with DSM5 alcohol use disorder, severe Admitted to BWF inpatient withdrawal management unit (Addiction Recovery Program) Exclusion Criteria: Any psychotic disorder, bipolar disorder, active suicidality or homicidality Inability to perform consent due to impaired mental status Clinical Institute Withdrawal Assessment (CIWA) score > 20 at any point in the ED Alcohol withdrawal seizure prior to or during the ED visit Systolic blood pressure persistently elevated above 180mmHg, or heart rate >130bmp, in the ED History of hypersensitivity to ketamine, or experience of emergence reaction History of any illicit or recreational use of ketamine Receipt of ketamine treatment for depression in the past 3 months History of DSM5 hallucinogen use disorder, intracranial mass or bleed, porphyria, thyrotoxicosis, seizure disorder other than from alcohol withdrawal, liver cirrhosis, renal failure, obstructive lung disease, or sleep apnea History within 6 months of head trauma, stroke, or myocardial infarction Liver dysfunction with LFTs >3x upper normal limit Current use of medications with known drug-drug interactions with ketamine (i.e., St. John's Wort, theophylline, opioid analgesics, CNS depressants other than benzodiazepines or phenobarbital) Pregnant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>This arm will receive ketamine (n=25) | Drug: Ketamine<br>* The intervention will consist of a single infusion of ketamine in the ED at a dose of 0.8mg/kg over 40 minutes.<br>|
| Placebo Comparator: Placebo<br>This arm will receive the saline placebo (n=25) | Drug: Saline<br>* The placebo will be a 0.9% saline solution administered over 40 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of administering ketamine in the emergency department (ED) for alcohol use disorder (AUD) patients seeking detoxification | The incidence of severe adverse events (AE), defined as either hypertensive urgency (systolic blood pressure>180mmHg or diastolic blood pressure>110mmHg) or tachycardia (heart rate>130bpm). Adequate safety will be defined as <10% of participants experiencing severe AEs. | Outcomes will be assessed throughout the inpatient admission, on average 3-5 days and throughout duration of study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dissociative effects | Clinician-Administered Dissociative States Scale (CADSS) | Baseline, daily during inpatient (average 3-5 days), 28 days, and 3, 6, and 12 months after inpatient treatment. | 
| Alcohol withdrawal | Clinical Institute Withdrawal Assessment (CIWA) | Assessed during the inpatient admission, on average 3-5 days. | 
| Craving for alcohol | Alcohol craving questionnaire | Assessed during the inpatient admission, on average 3-5 days; 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Craving for ketamine | Visual analog scale | Assessed during the inpatient admission, on average 3-5 days; 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Cue-induced craving | Visual analog scale will be used to rate the craving following a standardized protocol used to assess cue reactivity. The cue exposure procedure will end with a standardized relaxation exercise. | Assessed during the inpatient admission, on average 3-5 days; 28 days after treatment | 
| Preliminary efficacy of ketamine on days to alcohol relapse | Days to relapse will be measured by using the Timeline Follow-Back (TLFB). | 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Preliminary efficacy of ketamine on proportion heavy drinking days | The proportion of heavy drinking days will be measured by using the Timeline Follow-Back (TLFB). | 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Preliminary efficacy of ketamine on engagement with addiction treatment | The Alcoholic Anonymous Affiliation Scale (AAAS) will be used to measure engagement with addiction treatment. This is a 9-item scale to measure the degree of involvement with Alcoholics Anonymous. | Measured at baseline, 28 days, and 3, 6, and 12 months post treatment. | 
| Ketamine in Urine | Urine drug screen that includes ketamine will be assessed. | At baseline and 28 days after treatment | 
| Urine ethylglucuronide | Urine ethylglucuronide (EtG) will be obtained | At baseline and at 28 days after treatment | 
| Phosphatidylethanol (PEth) | Serum phosphatidylethanol (PEth) | At baseline and at 28 days after treatment | 
| Behavior Change Mechanisms | Mechanisms of behavior change will be measured using tools from the Science of Behavior Change Measures. | Once during inpatient treatment and at 28 days after treatment | 
| Anxiety | We will assess anxiety levels utilizing a 7-item scale (Generalized Anxiety Disorder - 7 (GAD-7)) | At baseline, each day during treatment (3-5 Days on average), 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Depression | We will assess depression levels utilizing a 9-item scale (Patient Health Questionnaire-9 (PHQ-9)) | At baseline, each day during treatment (3-5 Days on average), 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Suicidal Ideation | Columbia Suicide Severity Rating Scale (C-SSRS) will be used to assess suicidal Ideation | At baseline, each day during treatment (3-5 Days on average), 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Post Traumatic Stress | A patient self-report tool developed to examine PTSD symptoms in general medical settings (Abbreviated PTSD Checklist - Civilian Version) | Once during treatment | 
| Study Drug Side Effects | We will use Patient Rated Inventory of Side Effects (PRISE) to qualify side effects in the following domains: gastrointestinal, heart, skin, nervous system, eyes/ears, genital/urinary, sleep, sexual functioning, and other. Each domain has multiple symptoms which can be endorsed. For each domain the patient rates whether the symptoms are tolerable or distressing. | At baseline, each day during treatment (3-5 Days on average), 7, 14, 28 days and 3, 6, and 12 months after treatment | 
| Spirituality | We will use a 23-item measure to assess spirituality (Spirituality Scale). | Baseline, once during treatment, and at 28 days post treatment. |