Dual-Orexin Antagonism as a Mechanism for Improving Sleep and Drug Abstinence in Opioid Use Disorder

Study Overview
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Brief Summary
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Summary of Study Protocol. This project is designed to test neurobehavioral mechanisms underlying effects of the dual orexin-1/2 receptor antagonist suvorexant on sleep efficiency and opioid abstinence, and whether these outcomes are independent of one another. This will be the first study to investigate whether suvorexant improves outpatient opioid abstinence and sleep efficiency; and whether improving sleep mediates the improved opioid abstinence outcome. 120 participants with opioid use disorder (OUD) will complete this intent-to-treat study.

Detailed Description
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Study Design. Using a placebo-controlled, parallel-group, randomized clinical trial design, we will prospectively evaluate whether nightly treatment with the orexin-1/2 receptor antagonist suvorexant (20 mg/day PO), relative to placebo, can increase outpatient opioid abstinence and improve sleep efficiency (sleep time per time-in-bed) as a mediator/moderator among patients with OUD. We include current medication for treating OUD, as well as treatment site, as stratification factors in the group allocation. Using power and sample size calculations, we estimate that 120 participants will suffice to test our hypotheses. The study aims to test three co-primary hypotheses: Hypothesis 1: Relative to placebo, suvorexant (20 mg/day) will significantly increase percentage opioid abstinence during outpatient weeks 1-13. Hypothesis 2: Relative to placebo, suvorexant will improve sleep efficiency. Hypothesis 3: Higher inpatient sleep efficiency will be associated with increased outpatient opioid abstinence (independent of experimental group assignment).

Official Title
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Dual-Orexin Antagonism as a Mechanism for Improving Sleep and Drug Abstinence in Opioid Use Disorder

Conditions
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Opioid-use Disorder, Sleep

Intervention / Treatment
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* Drug: Suvorexant
* Drug: Suvorexant Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 years old Males and non-pregnant females who agree to medically accepted birth control for the duration of the study Meet DSM-5 criteria for opioid use disorder (any severity level) alone or comorbid with stable medical diseases (except for certain medications [see below]) Exclusion Criteria: Body mass index >38 Acute/unstable illness: conditions making it unsafe for participation, conditions with potential to disturb sleep (i.e. acute pain, respiratory infection) Chronic illnesses; renal failure, liver disease, seizures, and dementing illnesses Current psychiatric disease: psychosis, bipolar disorder, PTSD Smoking during the night (11pm-7am). Nicotine replacement therapy is allowed Medications including anxiolytics, hypnotics (both prescription and OTC), sedating antidepressants, anticonvulsants, sedating H1 antihistamines (non-sedating second generation H4 antihistamines are allowed), systemic steroids, respiratory stimulants and decongestants, prescription and OTC stimulants, prescription and OTC diet aids, herbal preparations, and narcotic analgesics. All medications and doses will be documented Sleep-disordered breathing and periodic leg movements (PLMs) defined as ≥ 10 apnea-hypopneas or PLM events related to EEG arousal per hour of sleep time, or any other primary sleep (e.g. narcolepsy, restless legs syndrome) or circadian disorder Night-shift work, which would alter circadian rhythm and be a confound in this trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomly assigned to one of the 2 parallel groups for the duration of the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Suvorexant placebo<br>Placebo (inert) tablet | Drug: Suvorexant Placebo<br>* Suvorexant Placebo<br>|
| Experimental: Suvorexant 20mg<br>Suvorexant 20mg tablet | Drug: Suvorexant<br>* In each group, the participant will take 1 tablet (placebo or 20mg) 30 minutes before bedtime.<br>* Other names: Belsomra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid abstinence | Percentage of opioid-free urine drug screens (UDS) | up to 13 weeks | 
| Sleep efficiency | Sleep efficiency equals sleep time (determined by standardized scoring of electroencephalogram recordings) divided by time in bed | Sleep efficiency is measured on the evening of the first medication dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily sleep questionnaire | Morning (post-awakening) assessment of sleep quality | Change in sleep quality scores from inpatient stay to outpatient weeks 2, 6 and 10 | 
| Actigraphic assessment of sleep | Actigraphic assessment of motion (activity counts), measured with Actiwatch and scoring software; motion is absent during sleep. | Change in total activity counts across outpatient weeks 2, 6 and 10 | 
| Weekly sleep questionnaire | Retrospective (past-week) self-report of sleep quality on each of 4 outpatient weeks | Change in sleep quality scores across outpatient weeks 1, 4, 8 and 12 | 
| Timeline followback interview assessment of substance use | Percentage of outpatient weeks with substance use (opioids, methadone, buprenorphine, cocaine metabolites, benzodiazepines, barbiturates, cannabinoids, amphetamines) | Once weekly (in conjunction with urine drug screen) on outpatient weeks 1 through 13 | 
| Urinary cortisol | Change in cortisol levels in picogram per milliliter (pg/ml) across 24 hour interval used to measure circadian rhythm | Measured at 11pm on nights 4, 6, 8 (coordinated with sleep efficiency and melatonin assessments) and the following day (7am and 3pm on days 5, 7, 9) on the inpatient unit | 
| Urinary melatonin | Change in melatonin levels in picograms per milliliter (pg/ml) across 24 hour interval used to measure circadian rhythm | Measured at 11pm on nights 4, 6, 8 (coordinated with sleep efficiency and cortisol assessments) and the following day (7am and 3pm on days 5, 7, 9) on the inpatient unit | 
| Clinical Global Impression (CGI) | CGI subscale scores for improvement and severity. Each subscale is scored on a 1-7 scale. Higher scores indicate worse (more severe) outcomes. | Change in CGI subscale scores across outpatient weeks 4, 8, and 12 | 
| Short Form-36 v2 Health Survey | Overall health assessment. The 36 items are grouped into 8 dimensions: physical functioning, physical and emotional limitations, social functioning, bodily pain, general and mental health. Each scale is directly transformed into a 0-100 scale. Lower scores on each scale indicate greater disability. | Change in overall health total score across outpatient weeks 4, 8, and 12 | 
| Medication satisfaction | Assessment of satisfaction with assigned medication condition, on 1-7 Likert scale. Higher scores indicate greater medication satisfaction. | Change in medication satisfaction score across outpatient weeks 4, 8, and 12 |