The United States opioid crisis has rapidly unfolded with more than two million Americans suffering from opioid use disorder (OUD), a serious, chronic illness. The leading cause of accidental death, OUD claims more than 130 lives per day (more than 40,000 annually). More than 50 million adults suffer from chronic pain, which puts them at highest risk for misusing opioids and developing OUD. Unfortunately, OUD treatment has a high failure rate, recapitulating the cycle of opioid abuse, abstinence, and relapse. The urgency to mitigate the opioid epidemic necessitates the need to delineate modifiable factors contributing to OUD, addiction, and response to treatment that could serve as potential intervention targets.
Sleep deficiency – characterized by insufficient or disrupted sleep, sleep disorders, or circadian disruption – occurs with extraordinarily high prevalence in OUD and affects approximately 75 percent of patients. Neurobiological and pharmacological substrates underlying addiction, physical dependence and withdrawal – including reward/reinforcement, risk taking behavior/mood regulation, autonomic regulation/integration, pain perception, and signaling in neuropharmacological pathways – overlap with several mechanisms controlling sleep and circadian regulation. Clinically, the relationship of OUD and sleep deficiency is bi-directional; opioids disrupt sleep and, during phases of abstinence and withdrawal, sleep deficiency and disturbances are magnified. In turn, sleep deficiency may influence the susceptibility to opioid overuse and dependence. Sleep deficiency intersects across the OUD trajectory – from medical/recreational use to misuse, addiction, withdrawal, recovery, relapse, overdose and death.
There are several specific ways in which sleep and circadian rhythm dysfunction can contribute and intersect with chronic pain and OUD. For example, sleep deficiency predisposes patients to “hyperalgesia” or increased pain sensitivity to noxious stimuli. Sleep deprivation also alters specific regions of the brain that control reward or pleasure-seeking behavior. The circadian clock may govern certain behavioral and molecular mechanisms that contribute to the pathophysiology of OUD. There are also shared neurochemical systems and brain regions implicated in the withdrawal from opioids and sleep. Finally, opioids contribute to sleep disordered breathing. Opioids result in respiratory depression and central sleep apnea, relationships that occur in a graded, dose-dependent manner and are tied to sleep architectural alterations, chemosensitivity, and ventilatory responses to arousals.
There is growing evidence and scientific consensus that alterations in sleep and circadian neurobiology contribute substantially to OUD during the active disease state as well as during recovery and relapse. In fact, results of a 2018 public FDA meeting directly involving patients with OUD revealed that sleep disturbance is a central contributing factor to opioid use relapse and treatment attrition. To address this public health crisis, the NIH launched the Helping to End Addiction Long-termSM (HEAL) program, a comprehensive effort to accelerate discovery of scientific strategies to effectively combat opioid addiction and develop approaches to more effectively manage pain. As part of the HEAL initiative, $25 million has been dedicated to directly fund sleep-specific research efforts through a program entitled, “Sleep and Circadian-Dependent Mechanisms Contributing to Opiate Use Disorder (OUD) and Response to Medication Assisted Treatment”.
Key existing knowledge gaps and areas of research priority in sleep deficiency and OUD include characterizing underlying neurobiological mechanisms, identifying risk biomarkers of opioid-induced sleep-disordered breathing and prolonged apneas, understanding intermediary pathways of pain and investigating the impact of pharmacological (ampakines, orexin antagonists, intranasal leptin, chronobiology of pharmacotherapeutics) and non-pharmacological (cognitive behavioral therapy targeting insomnia) strategies on OUD trajectory traversing addiction, withdrawal, recovery and relapse. Pursuing these avenues of research would allow for the opportunity to incorporate sleep and circadian rhythms into prevention and treatment models for OUD to improve outcomes at the individual and public health levels.
Reena Mehra, MD
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Chair, American Thoracic Society Assembly on Sleep and Neurobiology
Mariska Brown, PhD
Director of the National Center on Sleep Disorder Research, National Institutes of Health
Aaron Laposky, PhD
Program Director, Sleep& Neurobiology at National Institutes of Health
Gregory P Downey, MD FRCP(C), ATSF
National Jewish Health and University of Colorado
President, American Thoracic Society
