Funded Projects

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Project # Project Title Research Focus Area Research Program Administering IC Institution(s) Investigator(s) Location(s) Year Awarded
1R01DA059471-01
Medications for Opioid Use Disorder Differentially Modulate Intrinsically Photosensitive Retinal Ganglion Cell Function, Sleep, and Circadian Rhythms: Implications for Treatment New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIDA UNIVERSITY OF ALABAMA AT BIRMINGHAM CROPSEY, KAREN L (contact); GAMBLE, KAREN L Birmingham, AL 2023
NOFO Title: HEAL Initiative: Sleep Predictors of Opioid-Use Disorder Treatment Outcomes Program (R01 Clinical Trial Optional)
NOFO Number: RFA-DA-23-059
Summary:

People who use opioids, as well as those who take medications approved by the U.S. Food and Drug Administration for opioid use disorder (OUD), report significant problems with sleep and biological rhythms. This project will explore the activity of a novel group of photosensitive neurons in the retinas, a potential source for sleep disturbances in these individuals. The research could lead to new treatment strategies and responses, but also may identify a non-invasive, circadian biomarker to predict recovery and relapse in people with OUD.
1U01DA059472-01
Value of Sleep Metrics in Predicting Opioid Use Disorder Treatment Outcomes: Leadership and Data Coordinating Center New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIDA HARVARD PILGRIM HEALTH CARE, INC. WANG, RUI (contact); PURCELL, SHAUN M; REDLINE, SUSAN S Canton, MA 2023
NOFO Title: HEAL Initiative - Sleep Predictors of Opioid-Use Disorder Treatment Outcomes Program: Leadership and Data Co-ordinating Center (U01 Clinical Trial Optional)
NOFO Number: RFA-DA-23-060
Summary:

Chronic opioid use has well-known effects on sleep quality and circadian rhythms, but few predictive metrics core to mental and physical health and well-being are available to guide treatment with medications for opioid use disorder (OUD). This project will identify observable characteristics related to sleep and circadian rhythms that predict OUD treatment outcomes, toward refining treatment strategies and developing new ones. This data coordinating center will ensure that (1) high quality and standardized data are collected across all research sites, (2) all milestones and regulatory requirements are met, (3) study results are reported in a timely manner, and (4) that data and results are disseminated broadly.
1R01DA059465-01
The Impact of Central Sleep Apnea in Patients Receiving Medications for Opioid Use Disorder New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIDA UNIVERSITY OF PITTSBURGH PATEL, SANJAY R Pittsburgh, PA 2023
NOFO Title: HEAL Initiative: Sleep Predictors of Opioid-Use Disorder Treatment Outcomes Program (R01 Clinical Trial Optional)
NOFO Number: RFA-DA-23-059
Summary:

Medications used to treat opioid use disorder (OUD) such as methadone and buprenorphine can cause central sleep apnea—a condition in which an individual momentarily stops breathing during sleep. This project will evaluate whether central sleep apnea, by worsening sleep quality and causing low blood oxygen levels, leads to nighttime arousal and emotional distress, which in turn increases the risk of relapse in individuals receiving treatment for OUD.
1R01DA059469-01
Investigating Mechanisms Underpinning Outcomes in People on Opioid Agonist Treatment for OUD: Disentangling Sleep and Circadian Rhythm Influences on Craving and Emotion Regulation New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIDA EMMA PENDLETON BRADLEY HOSPITAL CARSKADON, MARY A (contact); MCGEARY, JOHN E; RICH, JOSIAH D Providence, RI 2023
NOFO Title: HEAL Initiative: Sleep Predictors of Opioid-Use Disorder Treatment Outcomes Program (R01 Clinical Trial Optional)
NOFO Number: RFA-DA-23-059
Summary:

Sleep and circadian rhythms are understudied risk factors for opioid use disorder (OUD) and its treatment. Opioids affect sleep quality in a way that can inhibit recovery. The two most effective medications for OUD also cause sleep problems. This project will increase understanding about underlying circadian and behavioral mechanisms, such as changes in craving and/or the ability to regulate emotions, that link poor sleep with suboptimal opioid treatment response outcomes.
1R01DA059473-01
Sleep and Circadian Rhythm Phenotypes and Mechanisms Associated With Opioid Use Disorder Treatment Outcomes New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIDA JOHNS HOPKINS UNIVERSITY HUHN, ANDREW S (contact); RABINOWITZ, JILL ALEXANDRA Baltimore, MD 2023
NOFO Title: HEAL Initiative: Sleep Predictors of Opioid-Use Disorder Treatment Outcomes Program (R01 Clinical Trial Optional)
NOFO Number: RFA-DA-23-059
Summary:

Chronic opioid use has well known effects on sleep quality, including disordered breathing during sleep and other abnormalities related to circadian rhythms. However, little is known about the relationship between sleep-related symptoms and non-medical opioid use among individuals being treated for opioid use disorder. This longitudinal study aims to identify biological pathways that may account for these associations. The research will first determine associations of sleep and proxy measures of circadian rhythms with non-medical opioid use. Second, they will investigate emotional processes associated with sleep/circadian symptoms and opioid treatment outcomes.
3UG1DA050072-02S2
Transitions Clinic Network: Post Incarceration Addiction Treatment, Healthcare, and Social Support (TCN PATHS) study New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIDA YALE UNIVERSITY Wang, Emily Ai-hua New Haven, CT 2020
NOFO Title: Notice of Special Interest (NOSI): NHLBI and NIDA Announce Availability of Administrative Supplements for HEAL Awardees to Address Sleep Impairments in OUD Treatment Response and Recovery Outcomes
NOFO Number: NOT-HL-20-746
Summary:

All forms of sleep deficiency can affect OUD treatment engagement and retention among people with OUD, particularly among people recently released from jail. Sleep deficiency may lead to a wide range of physical and psychological perturbations that may increase the likelihood of illicit opioid use, and disengagement in OUD treatment. This study will examine the association between sleep deficiency and OUD treatment retention in a sample of people receiving medications for OUD who were recently released from jail, to reduce morbidity and mortality from OUD among justice-involved individuals. The underlying rationale for this study is that sleep deficiency must be addressed in a holistic manner to support OUD treatment engagement. The specific aims are to 1) determine the prevalence of sleep deficiency and describe the sleep environment of a sample of people on MOUD recently released from jail; 2) estimate the association between sleep deficiency and OUD treatment retention; and 3) examine sleep environment as a potential mediator of sleep deficiency and OUD treatment retention in people recently released from jail. If successful, this study will provide data for the future development and testing of patient-centered interventions focusing on sleep deficiency among OUD treatment participants that enhance their retention in treatment
3UG3DA050325-02S1
Use of a GLP-1 Agonist to Treat Opioid Use Disorder in Rats and Man New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIDA PENNSYLVANIA STATE UNIV HERSHEY MED CTR GRIGSON, PATRICIA SUE ; BUNCE, SCOTT C Hershey, PA 2020
NOFO Title: Notice of Special Interest (NOSI): NHLBI and NIDA Announce Availability of Administrative Supplements for HEAL Awardees to Address Sleep Impairments in OUD Treatment Response and Recovery Outcomes
NOFO Number: NOT-HL-20-746
Summary:

Opioid use disorder, a chronic and relapsing disease, is a significant and escalating public health concern. But, despite the availability of approved pharmacotherapies and promising therapeutic interventions, the high rates of relapse indicate a critical need for a better understanding of the factors that contribute to relapse to opioids, and for the development of new treatment approaches. Sleep problems are a common symptom in most substance use disorder syndromes, including opioid use disorder (OUD), but they are severely undertreated, partly because the standard hypnotic medications used to treat sleep disorders are themselves addictive. This study will investigate whether activating the glucagon-like peptide-1 receptor pathway can help reduce craving while improving sleep in OUD patients. The FDA-approved medication liraglutide, a GLP-1R agonist, is currently approved to treat Type II diabetes mellitus and obesity in humans. This proposal for a supplemental study will add polysomnography, the gold-standard for evaluating sleep architecture, to an ongoing study. If successful, this study will provide a strong rationale for conducting a full multi-site, Phase III clinical trial.
1U01HL150835-01
Evaluating the Role of the Orexin System in Circadian Rhythms of Sleep and Stress in Persons on Medication-Assisted Treatments for Opioid Use Disorder New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI Johns Hopkins University HUHN, ANDREW S (contact); FINAN, PATRICK Baltimore, MD 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (U01 Clinical Trial Optional)
NOFO Number: RFA-HL-19-029
Summary:

For individuals with moderate to severe opioid use disorder (OUD), medication-assisted treatments (MATs) such as oral methadone and extended-release naltrexone (XR-NTX) are the gold standard in initiating and maintaining long-term recovery. Still, many patients struggle with persistent sleep disturbance and stress reactivity in the early stages of recovery, which drive relapse behaviors. This proposal constitutes a novel mechanistic approach to understanding the role of the orexin system in sleep disturbance and circadian rhythms of stress in OUD patients who are maintained on MATs and are early in recovery. This study will determine whether the FDA-approved sleep medication suvorexant (SUVO) improves sleep continuity and decreases diurnal measures of stress, and whether improvement of sleep/stress processes translates to improved OUD treatment outcomes. Its findings will fill critical gaps in our understanding of the role of the orexin system in sleep disturbance and circadian rhythms of stress that impact OUD recovery.
1U01HL150568-01
Effects of experimental sleep disruption and fragmentation on cerebral Mu-opioid receptor function, Mu-opioid receptor agonist analgesia, and abuse liability. New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI Johns Hopkins University Smith, Michael T Baltimore, MD 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (U01 Clinical Trial Optional)
NOFO Number: RFA-HL-19-029
Summary:

Chronic pain and opioid use disorders (OUD) are burgeoning interrelated epidemics. Sleep disturbances are prevalent, treatable, and increasingly recognized as risk factors for both chronic pain and OUD. Sleep disruption impairs endogenous pain inhibition, linked to analgesic efficacy and rewarding properties of mu-opioid receptor (MOR) agonists. It is not known, however, whether sleep disturbance causally alters mechanisms that contribute to OUD risk. Sleep continuity disruption (SCD) and/or sleep fragmentation (SF) may alter cerebral MOR availability, and these forms of sleep disruption may increase OUD risk. This study aims to 1) evaluate whether experimental SCD and/or SF alter resting or pain-evoked MOR binding potential (BP) in brain regions associated with pain inhibition; 2) examine whether SCD and/or SF alters the analgesic response; and 3) determine whether MOR BP in brain regions of interest are associated with analgesia and abuse liability.
1R01HL150523-01
Deconstructing sleep disruption as a major risk factor for relapse in opioid use New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI Medical College of Wisconsin EVERSON, CAROL A (contact); OLSEN, CHRISTOPHER M; RAFF, HERSHEL Milwaukee, WI 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (R01 - Clinical Trial Not Allowed)
NOFO Number: RFA-HL-19-028
Summary:

Profound sleep disturbances during abstinence have long been suspected of perpetuating vulnerability to relapse of people who misuse or are addicted to opioids. An animal model has shown that long-term sleep deficiency results in a persistent state of physiological dysregulation that is expected to modify the biology of abstinence and increase relapse potential. This study seeks to discover how persistent sleep restriction during withdrawal from opioid use increases vulnerability to relapse in the animal model by testing whether persistent sleep restriction during abstinence from opioid use is sufficient to increase opioid drug seeking. The functional outcome measure will be the degree of mitigation of opioid seeking. These studies will provide a basis for novel translational approaches to target mechanisms that are demonstrated to cause increased vulnerability to relapse.
1R01HL150836-01
Sleep, opiate withdrawal and the N/OFQ - NOP system New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI SRI International KILDUFF, THOMAS S (contact); BRUCHAS, MICHAEL R Menlo Par, CA 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (R01 - Clinical Trial Not Allowed)
NOFO Number: RFA-HL-19-028
Summary:

The widespread misuse of opioids has underscored the need to develop nonaddicting pain medications. Chronic pain is a major factor contributing to insomnia, and sleep disruption due to chronic pain causes patients to seek relief, exacerbating the drive for prescription opioids. In opioid use disorder, withdrawal from opiates induces insomnia, posing an additional challenge for successful abstinence. This study aims to determine whether treatment of opioid withdrawal-induced insomnia with nociceptin/orphanin FQ receptor (NOPR) agonists will mitigate the drive for opiate use. A major component of the arousal/withdrawal circuitries resides in the locus coeruleus (LC), which expresses MOPRs. The study will determine whether and how the NOPR system engages LC circuits to reduce arousal and insomnia-related phenotypes and assess the hypotheses that 1) the NOPR system is a component of the endogenous sleep/wake regulatory system and 2) NOPR agonists can act as therapeutic interventions to reduce opiate use.
3U01MH114087-02S2
EVALUATING THE IMPACT OF CHANGES IN OPIOID PRESCRIBING ACROSS HEALTH SYSTEMS IMPLEMENTING ZERO SUICIDE New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NIMH Henry Ford Health System AHMEDANI, BRIAN KENNETH; SIMON, GREGORY E. DETROIT, MI 2018
NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

This supplement supports the goals of the current award, “An Evaluation of the National Zero Suicide Model Across Learning Healthcare Systems” (U01MH114087). Safety planning is a highly recommended practice within the Zero Suicide framework, but little is known about the effectiveness of the individual elements that can make up a safety plan, such as lethal means assessment, identification of supportive contacts, coping skills, warning signs, and sources of distraction. All of the documentation lives in text-based clinical narratives. This supplement will support development of new metrics using natural language processing to determine baseline rates, from which we can quantify the change in safety planning and lethal means assessment practice longitudinally after implementation of new safety planning templates using our Zero Suicide main award.
1U01HL150596-01
The Collaboration Linking Opioid Use Disorder and Sleep ("CLOUDS") Study New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI Yale University YAGGI, HENRY KLAR (contact); BARRY, DECLAN T; REDEKER, NANCY S; SCHEINOST, DUSTIN New Haven, CT 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (U01 Clinical Trial Optional)
NOFO Number: RFA-HL-19-029
Summary:

Opioid use disorder (OUD) is a chronic and relapsing brain disease that affects over 2 million Americans. Despite effective evidence-based treatments in the form of behavioral interventions and FDA-approved medication for addiction treatment (MAT), relapse rates are high. The Collaboration Linking Opioid Use Disorder and Sleep Study will investigate patients on MAT to elucidate potential causal mechanisms between sleep deficiency and OUD. The aims of this study are to 1) test whether there are different neurocognitive connectivity patterns between patients with adequate vs. deficient sleep in brain systems involved in addiction and assess the extent to which these “neural fingerprints” predict ongoing opioid use; 2) evaluate the potential biologic, psychiatric, and pharmacologic mechanisms that explain the causal pathway between sleep deficiency and opioid use; and 3) test ecologic factors such as psychosocial, family, and neighborhood contextual factors associated with OUD and their contribution to sleep deficiency among patients in MAT.
1U01HL150551-01
Dual-orexin antagonism as a mechanism for improving sleep and drug abstinence in opioid use disorder New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI Wayne State University GREENWALD, MARK K (contact); ROEHRS, TIMOTHY A Detroit, MI 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (U01 Clinical Trial Optional)
NOFO Number: RFA-HL-19-029
Summary:

FDA-approved medications for treating opioid use disorder are effective, but there is a significant unmet need for alternatives, especially relapse prevention. NIDA and the FDA have encouraged investigators to expand the range of therapeutic outcomes, beyond measurement of abstinence. Insomnia is a clinically significant, but understudied, correlate/predictor of relapse to substance use. Yet most medications for treating insomnia have limited efficacy and can produce side effects. The orexin (OX) system plays a key role in sleep and substance use, offering a promising avenue for study. This project will address whether OX-1/2 antagonism is a mechanism that can directly improve outpatient opioid abstinence, or whether OX antagonism corrects sleep deficiencies and indirectly improves opioid abstinence. Specific aims are to determine whether nightly treatment with the OX-1/2 antagonist suvorexant, relative to placebo, 1) increases outpatient opioid abstinence and 2) improves sleep efficiency on the residential detoxification unit. The study will also determine 3) whether improved sleep efficiency predicts greater opioid abstinence (regardless of group assignment).
1R01HL150432-01
Cell-type specific role of circadian-dependent transcription in fentanyl-induced synaptic and behavioral plasticity New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI Boston University Logan, Ryan W Boston, MA 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (R01 - Clinical Trial Not Allowed)
NOFO Number: RFA-HL-19-028
Summary:

Among the most common symptoms experienced by individuals suffering with opioid use disorder (OUD) are severe sleep and circadian disruptions. The relationship between opioid dependence and sleep and circadian systems is not well understood. A circadian-dependent mechanism has been shown to modulate fentanyl reward-related behaviors in the nucleus accumbens (NAc). The study team will use a combination of behavioral, slice electrophysiology, and molecular approaches to 1) investigate the role of the circadian transcription factor NPAS2 in medium spiny neurons with dopamine 1 (D1R-MSNs); 2) assess the impact of fentanyl on synaptic plasticity at D1R-MSNs and investigate whether NPAS2 mediates the potentiation of excitatory synapses at specific diurnal phases; 3) elucidate the cell-type-specific NPAS2-dependent transcriptional mechanisms of fentanyl-seeking and relapse behaviors; and 4) investigate whether NPAS2 rescue and buprenorphine medication-assisted treatment (MAT) improve fentanyl-induced sleep disturbances. This study will define the role for circadian-dependent transcriptional mechanisms and uncover the therapeutic potential of NPAS2 for opioid dependence and relapse.
1R01HL150566-01
Arousal circuitry and opiate-associated memories New Strategies to Prevent and Treat Opioid Addiction Sleep Dysfunction as a Core Feature of Opioid Use Disorder and Recovery NHLBI Stanford University DE LECEA, LUIS (contact); CHEN, XIAOKE Stanford, CA 2019
NOFO Title: HEAL Initiative: Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT) (R01 - Clinical Trial Not Allowed)
NOFO Number: RFA-HL-19-028
Summary:

Repetitive drug use forms powerful memories associating drug-evoked experiences with its proximal environmental cues. Memories are major obstacles for successfully treating addiction, since even after a prolonged period of abstinence, reexposure to such cues often triggers craving that promotes relapse. A polysynaptic pathway from the paraventricular nucleus of the thalamus (PVT) to the lateral hypothalamus (LH) has been shown to play a role in the maintenance of the opioid-associated memories. Hypocretin (Hcrt) neurons in the LH strongly innervate the PVT, required for maintaining wakefulness and involved in drug seeking. These factors may link sleep disorders in opioid addicts with their long-lasting drug-associated memories. This study will (1) determine whether Hcrt neurons in the LH are the major target; (2) examine whether manipulating the LH (Hcrt)-PVT pathway can effectively prevent relapse; and (3) test whether sleep intervention could be an effective strategy to prevent relapse.