Role of the Orexin Receptor System in Stress, Sleep and Cocaine Use

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness of a medication called suvorexant in reducing anxiety, improving sleep, and reducing cocaine cravings or cocaine use.

Detailed Description
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Preclinical research has established important functions for the orexin system in mediating arousal/sleep, stress, and cue-induced reinstatement of drug taking (e.g., relapse). The role of stress/anxiety and drug cue reactivity in human drug relapse is well established, but to date, the role of the orexin system in modulating these phenomena has not been examined in humans with substance use disorders (e.g., cocaine). The goal of the present first-in-human study will be to examine the effects of an orexin antagonist (suvorexant) on interactions among stress/anxiety, sleep, and drug-cue reactivity. The study will utilize a battery of highly sensitive, drug-specific, laboratory measures of drug cue reactivity (a relapse risk model), and well-established metrics of stress/anxiety and sleep. The hypothesis is that antagonism of the orexin system will attenuate the link between (1) stress/anxiety and drug cue reactivity, and (2) sleep and drug cue reactivity. These results will elucidate a unique biochemical mechanism for understanding relapse, and provide a potential medication target for relapse prevention.

Official Title
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Role of the Orexin Receptor System in Stress, Sleep and Cocaine Use

Conditions
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Cocaine Use Disorder, Anxiety

Intervention / Treatment
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* Drug: suvorexant
* Drug: Placebo (for suvorexant)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: meet current DSM-5 criteria for cocaine use disorder (CUD) of at least moderate severity (≥4 symptoms) Exclusion Criteria: current DSM-IV diagnosis of any psychoactive substance dependence other than cocaine, marijuana, or nicotine have a DSM-IV axis I psychiatric disorder or neurological disease or disorder requiring ongoing treatment and/or making study participation unsafe significant current suicidal or homicidal ideation medical conditions contraindicating administration of suvorexant (e.g., severe pulmonary disease, severe cardiovascular disease or clinically abnormal EEG, severe liver or kidney disease, seizure disorder, or sleep disorder - particularly narcolepsy) taking medications known to have significant drug interactions with the study medication(s) (e.g., MAO inhibitors, anticonvulsants, haloperidol, phenothiazines, anesthetics, and all sedatives) currently or recently (last 3 months) treated for substance use [other than cocaine or nicotine] or another psychiatric condition conditions of probation or parole requiring reports of drug use to officers of the court; (8) impending incarceration pregnant or nursing for female patients inability to read, write, or speak English [required for lab tasks and psychometric scales] unwillingness to sign a written informed consent form subjects with alcohol use disorders or are drinking > 7 alcoholic drinks per week. All subjects who are excluded will be given referral information to other local treatment programs.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 55 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: suvorexant<br>Subjects will receive suvorexant (10 mg week 1, 20 mg week 2), once daily at 10 PM. | Drug: suvorexant<br>* Subjects will receive suvorexant capsules (10 mg week 1, 20 mg week 2), once daily at 10 PM.<br>* Other names: Belsomra;|
| Placebo Comparator: Placebo<br>Subjects will receive placebo once daily at 10 PM. | Drug: Placebo (for suvorexant)<br>* Subjects will receive placebo capsules once daily at 10 PM.<br>* Other names: corn starch;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cue Reactivity as Assessed by the Attention Bias (AB) Task | The attention bias (AB) task is a saccade-based eye-tracking measurement, developed by the PI to assess attentional bias to drug cues. AB measures utilizing eye movements have produced moderate to robust effects for a broad class abused substances, including cocaine. The score ranges from 0 to 1. Higher scores indicate a worse outcome. | day 0 | 
| Cue Reactivity as Assessed by the Attention Bias (AB) Task | The attention bias (AB) task is a saccade-based eye-tracking measurement, developed by the PI to assess attentional bias to drug cues. AB measures utilizing eye movements have produced moderate to robust effects for a broad class abused substances, including cocaine. The score ranges from 0 to 1. Higher scores indicate a worse outcome. | day 7 | 
| Cue Reactivity as Assessed by the Attention Bias (AB) Task | The attention bias (AB) task is a saccade-based eye-tracking measurement, developed by the PI to assess attentional bias to drug cues. AB measures utilizing eye movements have produced moderate to robust effects for a broad class abused substances, including cocaine. The score ranges from 0 to 1. Higher scores indicate a worse outcome. | day 14 | 
| Total Sleep as Assessed by the Misfit Shine Device | Sleep activity is monitored with a 3-axis accelerometer inside the watch device (Misfit Shine), using a general heuristic based on time and motion. The device is waterproof and worn on the wrist 24 hrs per day. Data are downloaded to smartphone via Bluetooth. | day 0 | 
| Total Sleep as Assessed by the Misfit Shine Device | Sleep activity is monitored with a 3-axis accelerometer inside the watch device (Misfit Shine), using a general heuristic based on time and motion. The device is waterproof and worn on the wrist 24 hrs per day. Data are downloaded to smartphone via Bluetooth. | day 2 | 
| Total Sleep as Assessed by the Misfit Shine Device | Sleep activity is monitored with a 3-axis accelerometer inside the watch device (Misfit Shine), using a general heuristic based on time and motion. The device is waterproof and worn on the wrist 24 hrs per day. Data are downloaded to smartphone via Bluetooth. | day 4 | 
| Total Sleep as Assessed by the Misfit Shine Device | Sleep activity is monitored with a 3-axis accelerometer inside the watch device (Misfit Shine), using a general heuristic based on time and motion. The device is waterproof and worn on the wrist 24 hrs per day. Data are downloaded to smartphone via Bluetooth. | day 7 | 
| Total Sleep as Assessed by the Misfit Shine Device | Sleep activity is monitored with a 3-axis accelerometer inside the watch device (Misfit Shine), using a general heuristic based on time and motion. The device is waterproof and worn on the wrist 24 hrs per day. Data are downloaded to smartphone via Bluetooth. | day 9 | 
| Total Sleep as Assessed by the Misfit Shine Device | Sleep activity is monitored with a 3-axis accelerometer inside the watch device (Misfit Shine), using a general heuristic based on time and motion. The device is waterproof and worn on the wrist 24 hrs per day. Data are downloaded to smartphone via Bluetooth. | day 11 | 
| Total Sleep as Assessed by the Misfit Shine Device | Sleep activity is monitored with a 3-axis accelerometer inside the watch device (Misfit Shine), using a general heuristic based on time and motion. The device is waterproof and worn on the wrist 24 hrs per day. Data are downloaded to smartphone via Bluetooth. | day 14 | 
| Stress as Assessed by the DASS21 Self-report Questionnaire Stress Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the stress subscale is 0 to 42, with higher scores indicating worse outcome. | day 0 | 
| Stress as Assessed by the DASS21 Self-report Questionnaire Stress Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the stress subscale is 0 to 42, with higher scores indicating worse outcome. | day 2 | 
| Stress as Assessed by the DASS21 Self-report Questionnaire Stress Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the stress subscale is 0 to 42, with higher scores indicating worse outcome. | day 4 | 
| Stress as Assessed by the DASS21 Self-report Questionnaire Stress Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the stress subscale is 0 to 42, with higher scores indicating worse outcome. | day 7 | 
| Stress as Assessed by the DASS21 Self-report Questionnaire Stress Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the stress subscale is 0 to 42, with higher scores indicating worse outcome. | day 9 | 
| Stress as Assessed by the DASS21 Self-report Questionnaire Stress Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the stress subscale is 0 to 42, with higher scores indicating worse outcome. | day 11 | 
| Stress as Assessed by the DASS21 Self-report Questionnaire Stress Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the stress subscale is 0 to 42, with higher scores indicating worse outcome. | day 14 | 
| Anxiety as Assessed by the DASS21 Self-report Questionnaire Anxiety Subscale. | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the anxiety subscale is 0 to 42, with higher scores indicating worse outcome. | day 0 | 
| Anxiety as Assessed by the DASS21 Self-report Questionnaire Anxiety Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the anxiety subscale is 0 to 42, with higher scores indicating worse outcome. | day 2 | 
| Anxiety as Assessed by the DASS21 Self-report Questionnaire Anxiety Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the anxiety subscale is 0 to 42, with higher scores indicating worse outcome. | day 4 | 
| Anxiety as Assessed by the DASS21 Self-report Questionnaire Anxiety Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the anxiety subscale is 0 to 42, with higher scores indicating worse outcome. | day 7 | 
| Anxiety as Assessed by the DASS21 Self-report Questionnaire Anxiety Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the anxiety subscale is 0 to 42, with higher scores indicating worse outcome. | day 9 | 
| Anxiety as Assessed by the DASS21 Self-report Questionnaire Anxiety Subscale | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the anxiety subscale is 0 to 42, with higher scores indicating worse outcome. | day 11 | 
| Anxiety as Assessed by the DASS21 Self-report Questionnaire | DASS21 is a 21-item self-report questionnaire assessing the severity of clinically agreed upon core depression, anxiety, and stress symptoms. It is well validated in multiple languages and countries, and has been utilized in SUD treatment and withdrawal studies. Total score on the anxiety subscale is 0 to 42, with higher scores indicating worse outcome. | day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cue Reactivity as Assessed by the Cocaine Craving Questionnaire (CCQ) Brief | The Cocaine Craving Questionnaire (CCQ) Brief is a self-report, 14-item measure with five conceptual domains: Desire to Use, Intention to Use, Anticipation of Positive Outcome, Anticipation of Relief from Dysphoria, and Lack of Control over use. The measure is well validated and has been used in multiple studies of CUD. Total score ranges from 1 to 7. A higher score indicates a worse outcome. | day 0, day 7, and day 14 | 
| Sleep Quality as by the Pittsburg Sleep Quality Index (PSQI) | The Pittsburg Sleep Quality Index (PSQI) is an 18-item self-report measure of sleep, providing a well-validated and reliable measure of sleep quality, latency, duration, duration efficiency, and disturbance, and an overall summary. The overall summary score will be reported for this measure. The PSQI has been used in several studies of individuals with SUD, including cocaine. Total score ranges from 0-21, with a higher score indicating worse outcome. | day 0, day 2, day 4, day 7, day 9, day 11, and day 14 | 
| Stress/Anxiety as Assessed by Blood Pressure During the Cold Pressor Test (CPT) - Systolic Blood Pressure | Cold Pressor Test (CPT) reliably increases activity of the sympathetic nervous system and the HPA axis, and produces reliable increases in heart rate and cortisol. Subjects are requested to submerge the dominant arm up to the wrist or elbow in ice-cold water (0° to 4° C) for as long as possible with a maximum of 90 seconds. The procedure activates afferent nerves and elicits a CNS stress response. This procedure produces no lasting biological or psychological distress beyond the acute challenge period, and physiological effects return to baseline within 90 min. In fact, the CPT is used to study pain in children, and is considered a noninvasive, exempt educational experimental activity by the IRB of the University of Texas-Austin. It has been used extensively in cardiology, endocrinology, psychiatry, and psychology since 1940 as a challenge to the peripheral and central stress axis | day 0, day 7, and day 14 | 
| Stress/Anxiety as Assessed by Blood Pressure During the Cold Pressor Test (CPT) - Diastolic Blood Pressure | Cold Pressor Test (CPT) reliably increases activity of the sympathetic nervous system and the HPA axis, and produces reliable increases in heart rate and cortisol. Subjects are requested to submerge the dominant arm up to the wrist or elbow in ice-cold water (0° to 4° C) for as long as possible with a maximum of 90 seconds. The procedure activates afferent nerves and elicits a CNS stress response. This procedure produces no lasting biological or psychological distress beyond the acute challenge period, and physiological effects return to baseline within 90 min. In fact, the CPT is used to study pain in children, and is considered a noninvasive, exempt educational experimental activity by the IRB of the University of Texas-Austin. It has been used extensively in cardiology, endocrinology, psychiatry, and psychology since 1940 as a challenge to the peripheral and central stress axis. | day 0, day 7, and day 14 | 
| Stress/Anxiety as Assessed by Cortisol Level During the Cold Pressor Test (CPT) | Cold Pressor Test (CPT) reliably increases activity of the sympathetic nervous system and the HPA axis, and produces reliable increases in heart rate and cortisol. Subjects are requested to submerge the dominant arm up to the wrist or elbow in ice-cold water (0° to 4° C) for as long as possible with a maximum of 90 seconds. The procedure activates afferent nerves and elicits a CNS stress response. This procedure produces no lasting biological or psychological distress beyond the acute challenge period, and physiological effects return to baseline within 90 min. In fact, the CPT is used to study pain in children, and is considered a noninvasive, exempt educational experimental activity by the IRB of the University of Texas-Austin. It has been used extensively in cardiology, endocrinology, psychiatry, and psychology since 1940 as a challenge to the peripheral and central stress axis. | day 0, day 7, and day 14 | 
| Stress as Assessed by a Visual Analog Scale (VAS) for Stress | Score provided is the total score (0 to 300) across three items that are each on a 0-100 scale. A higher score indicates greater stress. | day 0, day 2, day 4, day 7, day 9, day 11, and day 14 | 
| Percent Medication Compliance as Assessed by the Medical Event Monitoring System (MEMS, Aprex Corporation) Bottles |  | day 2, day 4, day 7, day 9, day 11, and day 14 | 
| Percent Medication Compliance as Assessed by Pill Counts |  | day 2, day 4, day 7, day 9, day 11, and day 14 | 
| Percent Medication Compliance as Assessed by Analysis of Riboflavin Markers in Urine Samples |  | day 2, day 4, day 7, day 9, day 11, and day 14 | 
| Percent Medication Compliance as Assessed by Text Reminders and Replies | Text-based reminders to take the medication will be enabled via using a HIPAA secure texting service (Talksoft ©), used broadly in medical settings. Participants will be prompted each night at 10 PM to take their medication, and instructed to text back yes when they have taken their medication. | day 2, day 4, day 7, day 9, day 11, and day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cocaine, sleep, anxiety, craving, addiction, orexin, cue reactivity, suvorexant, Belsomra