Medications for opioid use disorder differentially modulate intrinsically photosensitive retinal ganglion cell function, sleep, and circadian rhythms: implications for treatment - PROJECT SUMMARY
About 100,000 people die annually in the U.S. because of opioid overdose or complications of opioid use disorder
(OUD). 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.
