Medications for Opioid Use Disorder Photosensitive Retinal Ganglion Cell Function, Sleep, and Circadian Rhythms: Implications for Treatment

Purpose

Opioid use disorder (OUD) is a treatable medical illness with three medications FDA approved for treatment. However, persons with OUD report significant sleep disturbance, even when treated with medications for opioid use disorder, leading to high rates of relapse. In this project, we will investigate a special set of photosensitive neurons in the retina as an underlying mechanism for circadian rhythm and sleep disturbance from opioid use and medications for OUD that could lead to novel intervention and improve treatment outcomes.

Conditions

  • Opioid Use Disorder
  • Sleep Disturbance

Eligibility

Eligible Ages
Between 18 Years and 80 Years
Eligible Genders
All
Accepts Healthy Volunteers
Yes

Inclusion Criteria

  1. Adults (18+) 2. prescribed one of three medications for opioid use disorder (methadone, XR-NTX, buprenorphine) or healthy control 3. stable on MOUD (no dose change) for the past month 4. positive on urine drug screen (UDS) for buprenorphine or methadone if prescribed those medications

Exclusion Criteria

  1. eye disease reported by history or noted on exam including disease of the anterior and posterior segment of the eye, cataracts, retinopathy, glaucoma, cataracts, amblyopia, scotoma, color or night blindness, corneal pathologies, macular degeneration, or retinitis pigmentosa; 2. acutely suicidal, manic, intoxicated, or otherwise not stable enough to provide informed consent 3. self-reported use of illicit opioids, stimulants (prescribed or illicit), or benzodiazepines/sedative/hypnotics in the past month 4. alcohol or cannabis use disorder measured as severe on The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Checklist 5. positive on UDS for illicit opioids (e.g., morphine, oxycodone, fentanyl),stimulants, benzodiazepines/sedative/hypnotics 6. shift workers who work outside normal 7 a.m. to 6 p.m. hours, according to the National Institute of Occupational Safety and Health (NIOSH) 7. persons diagnosed with narcolepsy

Study Design

Phase
Study Type
Observational
Observational Model
Cohort
Time Perspective
Prospective

Arm Groups

ArmDescriptionAssigned Intervention
MOUD therapy methadone 50 methadone participants
  • Other: Post-Illumination Pupillary Response (PIPR)
    The PIPR is measured in six, 80-s test periods in which the stimulus, either Blue (470 nm) or Red (623 nm), is presented to the dilated eye while the pupil response of the un-dilated eye is measured (consensual pupil response
    Other names:
    • PIPR
  • Other: Polysomnography
    Measure electroencephalography (EEG), electrooculography (EOG), electromyography (EMG), electrocardiography (ECG), respiratory channels (effort and nasal pressure), and oxygen saturation.
    Other names:
    • PSG
  • Other: Multiple Sleep Latency Test
    Assist in the diagnosis of disorders of hypersomnolence,63 it is also used in research to quantify daytime sleepiness and serves as a more objective measure of daytime sleepiness than self-report questionnaires
    Other names:
    • MSLT
  • Behavioral: Ecological Momentary Assessments
    Morning after overnight Visit 2, participants will complete ecological momentary assessments (EMAs) over a 10-day assessment period. Using EMA through the InsightTM mHealth platform to capture momentary craving, withdrawal and mood states across 10 days among persons who smoke and nonsmokers prior to an overnight procedures. Participants will complete morning and evening sleep diaries via the EMA InsightTM mHealth platform self-reported sleep and wake information, fatigue, naps, opioid craving and withdrawal.
    Other names:
    • EMA
  • Device: Actigraphy
    7-day actigraphy period will be used to determine the habitual sleep start and wake times. The CamNTech MotionWatch8 (Cambridge, UK) is a solid-state piezo-electric accelerometer that collects data on activity (i.e., arm motion) and ambient light.Actigraphy data are downloaded from the MotionWatch8 into the software (MotionWare) for analysis, management, and exportation. Bed and wake times will be entered by the subjects via a REDCap link and this information coupled with the sleep diary reports will be entered to determine sleep intervals. Algorithms in the Motion Watch 8 software will determine sleep start, sleep end, total sleep time (duration), sleep quality, sleep efficiency, wake after sleep onset, and sleep fragmentation
  • Other: DLMO
    Participants will be given an evening meal and then be accompanied to the UAB Highlands Hospital Sleep Unit by 5:30pm. The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels.Participants will be allowed to sleep in darkness until 8:00am, at which time they will be provided transportation.We will also bank frozen samples taken prior to the light exposure for later calculation of the Dim Light Melatonin Onset (DLMO), a circadian phase estimate.
    Other names:
    • Dim Light Melatonin Onset
  • Other: Melatonin Suppression Test
    The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels. Participants will be asked to refrain from caffeine consumption 12 hours before reporting to the sleep unit and will provide 2-3 ml of saliva every 30 minutes starting at 6:00pm and ending after the light exposure. For melatonin suppression, 2-hours light exposure will begin 2 hours before the calculated mid-sleep time. Collection saliva samples 1-h, 30-min, and immediately before the light exposure and every 30 min throughout exposure. Samples will be centrifuged and frozen/stored at -20ºC until assay and remaining samples stored at -80ºC. Melatonin levels will be assayed via the Buhlmann Direct Saliva Melatonin. Melatonin suppression will be calculated as the percent decrease from the sample taken immediately prior to the light exposure
MOUD therapy buprenorphine 50 buprenorphine participants
  • Other: Post-Illumination Pupillary Response (PIPR)
    The PIPR is measured in six, 80-s test periods in which the stimulus, either Blue (470 nm) or Red (623 nm), is presented to the dilated eye while the pupil response of the un-dilated eye is measured (consensual pupil response
    Other names:
    • PIPR
  • Other: Polysomnography
    Measure electroencephalography (EEG), electrooculography (EOG), electromyography (EMG), electrocardiography (ECG), respiratory channels (effort and nasal pressure), and oxygen saturation.
    Other names:
    • PSG
  • Other: Multiple Sleep Latency Test
    Assist in the diagnosis of disorders of hypersomnolence,63 it is also used in research to quantify daytime sleepiness and serves as a more objective measure of daytime sleepiness than self-report questionnaires
    Other names:
    • MSLT
  • Behavioral: Ecological Momentary Assessments
    Morning after overnight Visit 2, participants will complete ecological momentary assessments (EMAs) over a 10-day assessment period. Using EMA through the InsightTM mHealth platform to capture momentary craving, withdrawal and mood states across 10 days among persons who smoke and nonsmokers prior to an overnight procedures. Participants will complete morning and evening sleep diaries via the EMA InsightTM mHealth platform self-reported sleep and wake information, fatigue, naps, opioid craving and withdrawal.
    Other names:
    • EMA
  • Device: Actigraphy
    7-day actigraphy period will be used to determine the habitual sleep start and wake times. The CamNTech MotionWatch8 (Cambridge, UK) is a solid-state piezo-electric accelerometer that collects data on activity (i.e., arm motion) and ambient light.Actigraphy data are downloaded from the MotionWatch8 into the software (MotionWare) for analysis, management, and exportation. Bed and wake times will be entered by the subjects via a REDCap link and this information coupled with the sleep diary reports will be entered to determine sleep intervals. Algorithms in the Motion Watch 8 software will determine sleep start, sleep end, total sleep time (duration), sleep quality, sleep efficiency, wake after sleep onset, and sleep fragmentation
  • Other: DLMO
    Participants will be given an evening meal and then be accompanied to the UAB Highlands Hospital Sleep Unit by 5:30pm. The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels.Participants will be allowed to sleep in darkness until 8:00am, at which time they will be provided transportation.We will also bank frozen samples taken prior to the light exposure for later calculation of the Dim Light Melatonin Onset (DLMO), a circadian phase estimate.
    Other names:
    • Dim Light Melatonin Onset
  • Other: Melatonin Suppression Test
    The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels. Participants will be asked to refrain from caffeine consumption 12 hours before reporting to the sleep unit and will provide 2-3 ml of saliva every 30 minutes starting at 6:00pm and ending after the light exposure. For melatonin suppression, 2-hours light exposure will begin 2 hours before the calculated mid-sleep time. Collection saliva samples 1-h, 30-min, and immediately before the light exposure and every 30 min throughout exposure. Samples will be centrifuged and frozen/stored at -20ºC until assay and remaining samples stored at -80ºC. Melatonin levels will be assayed via the Buhlmann Direct Saliva Melatonin. Melatonin suppression will be calculated as the percent decrease from the sample taken immediately prior to the light exposure
MOUD therapy extended-release naltrexone 50 extended-release naltrexone (XR-NTX) participants
  • Other: Post-Illumination Pupillary Response (PIPR)
    The PIPR is measured in six, 80-s test periods in which the stimulus, either Blue (470 nm) or Red (623 nm), is presented to the dilated eye while the pupil response of the un-dilated eye is measured (consensual pupil response
    Other names:
    • PIPR
  • Other: Polysomnography
    Measure electroencephalography (EEG), electrooculography (EOG), electromyography (EMG), electrocardiography (ECG), respiratory channels (effort and nasal pressure), and oxygen saturation.
    Other names:
    • PSG
  • Other: Multiple Sleep Latency Test
    Assist in the diagnosis of disorders of hypersomnolence,63 it is also used in research to quantify daytime sleepiness and serves as a more objective measure of daytime sleepiness than self-report questionnaires
    Other names:
    • MSLT
  • Behavioral: Ecological Momentary Assessments
    Morning after overnight Visit 2, participants will complete ecological momentary assessments (EMAs) over a 10-day assessment period. Using EMA through the InsightTM mHealth platform to capture momentary craving, withdrawal and mood states across 10 days among persons who smoke and nonsmokers prior to an overnight procedures. Participants will complete morning and evening sleep diaries via the EMA InsightTM mHealth platform self-reported sleep and wake information, fatigue, naps, opioid craving and withdrawal.
    Other names:
    • EMA
  • Device: Actigraphy
    7-day actigraphy period will be used to determine the habitual sleep start and wake times. The CamNTech MotionWatch8 (Cambridge, UK) is a solid-state piezo-electric accelerometer that collects data on activity (i.e., arm motion) and ambient light.Actigraphy data are downloaded from the MotionWatch8 into the software (MotionWare) for analysis, management, and exportation. Bed and wake times will be entered by the subjects via a REDCap link and this information coupled with the sleep diary reports will be entered to determine sleep intervals. Algorithms in the Motion Watch 8 software will determine sleep start, sleep end, total sleep time (duration), sleep quality, sleep efficiency, wake after sleep onset, and sleep fragmentation
  • Other: DLMO
    Participants will be given an evening meal and then be accompanied to the UAB Highlands Hospital Sleep Unit by 5:30pm. The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels.Participants will be allowed to sleep in darkness until 8:00am, at which time they will be provided transportation.We will also bank frozen samples taken prior to the light exposure for later calculation of the Dim Light Melatonin Onset (DLMO), a circadian phase estimate.
    Other names:
    • Dim Light Melatonin Onset
  • Other: Melatonin Suppression Test
    The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels. Participants will be asked to refrain from caffeine consumption 12 hours before reporting to the sleep unit and will provide 2-3 ml of saliva every 30 minutes starting at 6:00pm and ending after the light exposure. For melatonin suppression, 2-hours light exposure will begin 2 hours before the calculated mid-sleep time. Collection saliva samples 1-h, 30-min, and immediately before the light exposure and every 30 min throughout exposure. Samples will be centrifuged and frozen/stored at -20ºC until assay and remaining samples stored at -80ºC. Melatonin levels will be assayed via the Buhlmann Direct Saliva Melatonin. Melatonin suppression will be calculated as the percent decrease from the sample taken immediately prior to the light exposure
Non-opioid using controls non-opioid using controls
  • Other: Post-Illumination Pupillary Response (PIPR)
    The PIPR is measured in six, 80-s test periods in which the stimulus, either Blue (470 nm) or Red (623 nm), is presented to the dilated eye while the pupil response of the un-dilated eye is measured (consensual pupil response
    Other names:
    • PIPR
  • Other: Polysomnography
    Measure electroencephalography (EEG), electrooculography (EOG), electromyography (EMG), electrocardiography (ECG), respiratory channels (effort and nasal pressure), and oxygen saturation.
    Other names:
    • PSG
  • Other: Multiple Sleep Latency Test
    Assist in the diagnosis of disorders of hypersomnolence,63 it is also used in research to quantify daytime sleepiness and serves as a more objective measure of daytime sleepiness than self-report questionnaires
    Other names:
    • MSLT
  • Behavioral: Ecological Momentary Assessments
    Morning after overnight Visit 2, participants will complete ecological momentary assessments (EMAs) over a 10-day assessment period. Using EMA through the InsightTM mHealth platform to capture momentary craving, withdrawal and mood states across 10 days among persons who smoke and nonsmokers prior to an overnight procedures. Participants will complete morning and evening sleep diaries via the EMA InsightTM mHealth platform self-reported sleep and wake information, fatigue, naps, opioid craving and withdrawal.
    Other names:
    • EMA
  • Device: Actigraphy
    7-day actigraphy period will be used to determine the habitual sleep start and wake times. The CamNTech MotionWatch8 (Cambridge, UK) is a solid-state piezo-electric accelerometer that collects data on activity (i.e., arm motion) and ambient light.Actigraphy data are downloaded from the MotionWatch8 into the software (MotionWare) for analysis, management, and exportation. Bed and wake times will be entered by the subjects via a REDCap link and this information coupled with the sleep diary reports will be entered to determine sleep intervals. Algorithms in the Motion Watch 8 software will determine sleep start, sleep end, total sleep time (duration), sleep quality, sleep efficiency, wake after sleep onset, and sleep fragmentation
  • Other: DLMO
    Participants will be given an evening meal and then be accompanied to the UAB Highlands Hospital Sleep Unit by 5:30pm. The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels.Participants will be allowed to sleep in darkness until 8:00am, at which time they will be provided transportation.We will also bank frozen samples taken prior to the light exposure for later calculation of the Dim Light Melatonin Onset (DLMO), a circadian phase estimate.
    Other names:
    • Dim Light Melatonin Onset
  • Other: Melatonin Suppression Test
    The sleep unit allows for strict control of light exposure (< 5 lux at eye level), room temperature and oral intake factors that could alter melatonin levels. Participants will be asked to refrain from caffeine consumption 12 hours before reporting to the sleep unit and will provide 2-3 ml of saliva every 30 minutes starting at 6:00pm and ending after the light exposure. For melatonin suppression, 2-hours light exposure will begin 2 hours before the calculated mid-sleep time. Collection saliva samples 1-h, 30-min, and immediately before the light exposure and every 30 min throughout exposure. Samples will be centrifuged and frozen/stored at -20ºC until assay and remaining samples stored at -80ºC. Melatonin levels will be assayed via the Buhlmann Direct Saliva Melatonin. Melatonin suppression will be calculated as the percent decrease from the sample taken immediately prior to the light exposure

Recruiting Locations

University of Alabama at Birmingham
Birmingham, Alabama 35233
Contact:
Brionna Smith, B.S.
205-975-7809
Cropseylab@uabmc.edu

More Details

Status
Recruiting
Sponsor
University of Alabama at Birmingham

Study Contact

Karen Cropsey, PsyD
205-975-7809
kcropsey@uabmc.edu

Detailed Description

Three medications for OUD (MOUD) are FDA-approved and regularly used to treat OUD: methadone, buprenorphine, and extended-release naltrexone (XR-NTX). However, persons who use opioids, including those prescribed MOUDs, report sleep disruption. In addition to the sleep centers of the brain, mu opioid receptors (MORs) are also expressed in the retina (including the human retina), specifically in ganglion cells that are critically important for non-image forming photoreception including circadian regulation of sleep-wake behavior. Pre-clinical studies show that activation of MORs on these intrinsically photosensitive retinal ganglion cells (ipRGCs) reduces the electrophysiological response to light, impacting critical ipRGC functions such as synchronization of sleep-wake behavior and circadian rhythms to light (photoentrainment), light-induced melatonin suppression, and the post-illumination pupillary reflex (PIPR). Together, these results suggest that activation of MORs in the ipRGCs by opioid use and/or MOUDs may impair downstream ipRGC functions. This multi-disciplinary study will examine the novel overarching hypothesis that persistent alterations in sleep/wake behavior in OUD patients undergoing treatment are mediated by impaired ipRGC function, and biomarkers of this pathway can predict recovery and relapse. Three aims will be tested in a sample of 200 participants, 150 of whom will be engaged in MOUD therapy (e.g., 50 each on methadone, buprenorphine, and XR-NTX, respectively) and 50 of whom will be non-opioid using control participants. Aim 1 will test the hypothesis that MOUD differentially impacts function of ipRGC responses. Aim 2 will examine whether MOUD differentially impacts daytime sleepiness, daily sleep-wake behavior, sleep architecture, and sleep-disordered breathing. Finally, Aim 3 will determine if ipRGC function predicts opioid relapse among MOUD groups at 1-, 3- and 6- month follow-up. Compared to non-opioid using controls or persons receiving an opioid antagonist (XR-NTX), we predict that participants who are receiving an agonist (methadone) or partial-agonist (buprenorphine) MOUD will have the most ipRGC interference, as evidenced by reduced PIPR, attenuated light-induced melatonin suppression, reduced circadian rhythmic amplitude, increased sleep latency, and increased sleep fragmentation. Importantly, we hypothesize that impaired ipRGC function will predict worse treatment outcomes as indicated by opioid use by 6-month follow-up. Finally, an exploratory aim will examine whether the MOUD groups show different relationships between opioid craving/withdrawal symptoms and sleep-wake behavior over a 10-day assessment of the participants' daily lives within the normal environment. The results of this study will be highly significant because it would support the use of the pupillary response to light and other indicators of ipRGC function as novel biomarkers to predict the response and outcomes to MOUDs.