Posted on by Lawrence Tabak, D.D.S., Ph.D.
Opioid use disorders (OUD) now threaten the health and lives of far too many young and adult Americans. While getting treatment is a key first step to recovery, overcoming an opioid addiction often comes with brutal withdrawal symptoms, including bad bouts of insomnia that are often untreatable with traditional prescription sleep medications. These medications act as sedatives, making them unsafe for people in OUD recovery.
But now, researchers have found that an approved drug for insomnia that works differently than other sleep medications could offer some needed help for the sleeplessness that affects those overcoming an opioid addiction . The drug, known as suvorexant (Belsomra ®), was provided in a study to people during and immediately after tapering off opioids, and it allowed them to sleep significantly more during this week-long period. Suvorexant also helped to reduce their opioid withdrawal and craving.
This study, which received support from NIH’s Helping to End Addiction Long-term (HEAL) Initiative certainly offers promising news. The Food and Drug Administration (FDA) approved suvorexant to treat insomnia in 2014, and it is available for off-label use to help people overcoming an OUD.
The good news, however, comes with a major caveat. This early clinical trial had relatively small enrollment numbers, and larger studies are definitely needed to follow up and confirm the initial results.
The latest findings, published in the journal Science Translational Medicine, come from a team at Johns Hopkins University School of Medicine, Baltimore, led by Andrew Huhn. He and colleagues recognized sleep disturbances as a severe problem during recovery. They wondered whether suvorexant might help.
Suvorexant doesn’t actively sedate people like other sleeping medications. Suvorexant works by targeting orexin, a biochemical made in the brain that helps keep you awake . Interestingly, orexin signals also have been implicated in opioid withdrawal symptoms, sleep disturbances, and drug-seeking behaviors.
Thirty-eight people entered the Hopkins study, and 26 completed it. Their average age was about 40, with close to equal numbers of white and Black participants. Most were male, and all were undergoing supervised withdrawal treatment with buprenorphine/naloxone, which is used in combination as a medication-assisted treatment for OUD.
To find out if suvorexant helped, the researchers measured total sleep time nightly using wireless devices that recorded brain activity and movement in people taking either 20 milligrams or 40 milligrams of suvorexant versus a placebo. The researchers also used standard methods to assess symptoms of opioid withdrawal, along with suvorexant’s potential for abuse.
The data showed that people taking suvorexant over four days while tapering off opioids slept about 90 minutes longer per night on average. They also continued to sleep for an extra hour a night on average in the four days following the tapering period. The researchers note that these increases in sleep duration far exceed the American Academy of Sleep Medicine’s threshold for clinically meaningful improvement.
The researchers also didn’t see any differences in adverse events between those taking suvorexant versus a placebo. They also note that the main side effect of suvorexant in general is feeling sleepy the next day as the drug wears off slowly. There also wasn’t any evidence that suvorexant might come with a risk for drug abuse.
However, because the study was small, it lacked the needed statistical power to determine meaningful differences between the two doses of suvorexant. The study also didn’t include many women. But overall, the evidence that suvorexant or even other medications that target orexin could improve OUD treatment appears quite promising.
The NIH’s HEAL Initiative has launched over 600 research projects across the country. These studies cover a range of science and health care needs. But a common thread running through these projects is a desire to enhance the evidence base for lifesaving OUD interventions. Another is a commitment to discover better ways to help people recover from an OUD, and these latest data on suvorexant show this commitment in action.
 Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper. Huhn AS, Finan PH, Gamaldo CE, Hammond AS, Umbricht A, Bergeria CL, Strain EC, Dunn KE. Sci Transl Med. 2022 Jun 22;14(650):eabn8238.
 The hypocretin/orexin system. Ebrahim IO, et al. J R Soc Med. 2002 May;95(5):227-30.
SAMHSA’s National Helpline (Substance Abuse and Mental Health Services Administration, Rockville, MD)
Opioids (National Institute on Drug Abuse/NIH)
Andrew Huhn (Johns Hopkins School of Medicine, Baltimore)
NIH Support: National Institute on Drug Abuse
Posted on by Dr. Francis Collins
As a cardiac electrophysiologist, Deeptankar DeMazumder has worked for years with people at risk for sudden cardiac arrest (SCA). Despite the latest medical advances, less than 10 percent of individuals stricken with an SCA will survive this highly dangerous condition in which irregular heart rhythms, or arrhythmias, cause the heart suddenly to stop beating.
In his role as a physician, DeMazumder keeps a tight focus on the electrical activity in their hearts, doing his best to prevent this potentially fatal event. In his other role, as a scientist at the University of Cincinnati College of Medicine, DeMazumder is also driven by a life-saving aspiration: finding ways to identify at-risk individuals with much greater accuracy than currently possible—and to develop better ways of protecting them from SCAs. He recently received a 2020 NIH Director’s New Innovator Award to pursue one of his promising ideas.
SCAs happen without warning and can cause death within minutes. Poor heart function and abnormal heart rhythms are important risk factors, but it’s not possible today to predict reliably who will have an SCA. However, doctors already routinely capture a wealth of information in electrical signals from the heart using electrocardiograms (ECGs). They also frequently use electroencephalograms (EEGs) to capture electrical activity in the brain.
DeMazumder’s innovative leap is to look at these heart and brain signals jointly, as well as in new ways, during sleep. According to the physician-scientist, sleep is a good time to search for SCA signatures in the electrical crosstalk between the heart and the brain because many other aspects of brain activity quiet down. He also thinks it’s important to pay special attention to what happens to the body’s electrical signals during sleep because most sudden cardiac deaths happen early in the waking hours, for reasons that aren’t well understood.
He has promising preliminary evidence from both animal models and humans suggesting that signatures within heart and brain signals are unique predictors of sudden death, even in people who appear healthy . DeMazumder has already begun developing a set of artificial intelligence algorithms for jointly deciphering waveform signals from the heart, brain, and other body signals [2,3]. These new algorithms associate the waveform signals with a wealth of information available in electronic health records to improve upon the algorithm’s ability to predict catastrophic illness.
DeMazumder credits his curiosity about what he calls the “art and science of healing” to his early childhood experiences and his family’s dedication to community service in India. It taught him to appreciate the human condition, and he has integrated this life-long awareness into his Western medical training and his growing interest in computer science.
For centuries, humans have talked about how true flourishing needs both head and heart. In DeMazumder’s view, science is just beginning to understand the central role of heart-brain conversations in our health. As he continues to capture and interpret these conversations through his NIH-supported work, he hopes to find ways to identify individuals who don’t appear to have serious heart disease but may nevertheless be at high risk for SCA. In the meantime, he will continue to do all he can for the patients in his care.
 Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Dey S, DeMazumder D, Sidor A, Foster DB, O’Rourke B. Circ Res. 2018;123(3):356-371.
 Entropy of cardiac repolarization predicts ventricular arrhythmias and mortality in patients receiving an implantable cardioverter-defibrillator for primary prevention of sudden death. DeMazumder D, Limpitikul WB, Dorante M, et al. Europace. 2016;18(12):1818-1828.
 Dynamic analysis of cardiac rhythms for discriminating atrial fibrillation from lethal ventricular arrhythmias. DeMazumder D, Lake DE, Cheng A, et al. Circ Arrhythm Electrophysiol. 2013;6(3):555-561.
Sudden Cardiac Arrest (National Heart, Lung, and Blood Institute/NIH)
Deeptankar DeMazumder (University of Cincinnati College of Medicine)
DeMazumder Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: National Heart, Lung, and Blood Institute; Common Fund
Posted on by Dr. Francis Collins
Getting plenty of deep, restful sleep is essential for our physical and mental health. Now comes word of yet another way that sleep is good for us: it triggers rhythmic waves of blood and cerebrospinal fluid (CSF) that appear to function much like a washing machine’s rinse cycle, which may help to clear the brain of toxic waste on a regular basis.
The video above uses functional magnetic resonance imaging (fMRI) to take you inside a person’s brain to see this newly discovered rinse cycle in action. First, you see a wave of blood flow (red, yellow) that’s closely tied to an underlying slow-wave of electrical activity (not visible). As the blood recedes, CSF (blue) increases and then drops back again. Then, the cycle—lasting about 20 seconds—starts over again.
The findings, published recently in the journal Science, are the first to suggest that the brain’s well-known ebb and flow of blood and electrical activity during sleep may also trigger cleansing waves of blood and CSF. While the experiments were conducted in healthy adults, further study of this phenomenon may help explain why poor sleep or loss of sleep has previously been associated with the spread of toxic proteins and worsening memory loss in people with Alzheimer’s disease.
In the new study, Laura Lewis, Boston University, MA, and her colleagues at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston. recorded the electrical activity and took fMRI images of the brains of 13 young, healthy adults as they slept. The NIH-funded team also built a computer model to learn more about the fluid dynamics of what goes on in the brain during sleep. And, as it turns out, their sophisticated model predicted exactly what they observed in the brains of living humans: slow waves of electrical activity followed by alternating waves of blood and CSF.
Lewis says her team is now working to come up with even better ways to capture CSF flow in the brain during sleep. Currently, people who volunteer for such experiments have to be able to fall asleep while wearing an electroencephalogram (EEG) cap inside of a noisy MRI machine—no easy feat. The researchers are also recruiting older adults to begin exploring how age-related changes in brain activity during sleep may affect the associated fluid dynamics.
 Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Science. 2019 Nov 1;366(6465):628-631.
Sleep and Memory (National Institute of Mental Health/NIH)
Sleep Deprivation and Deficiency (National Heart, Lung, and Blood Institute/NIH)
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
NIH Support: National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
Some people are early risers, wide awake at the crack of dawn. Others are night owls who can’t seem to get to bed until well after midnight and prefer to sleep in. Why is this? An NIH-funded team has some new clues based on evidence showing how a molecular “switch” wired into the biological clocks of extreme early risers leads them to operate on a daily cycle of about 20 hours instead of a full 24-hour, or circadian (Latin for “about a day”), cycle .
These new atomic-level details, shared from fruit flies to humans, may help to explain how more subtle clock variations predispose people to follow different sleep patterns. They also may lead to new treatments designed to reset the clock in people struggling with sleep disorders, jet lag, or night-shift work.
This work, published recently in the journal eLIFE, comes from Carrie Partch, University of California, Santa Cruz, and her colleagues at Duke-NUS Medical School in Singapore and the University of California, San Diego. It builds on decades of research into biological clocks, which help to control sleeping and waking, rest and activity, fluid balance, body temperature, cardiac rate, oxygen consumption, and even the secretions of endocrine glands.
These clocks, found in cells and tissues throughout the body, are composed of specialized sets of proteins. They interact in specific ways to regulate transcription of about 15 percent of the genome over a 24-hour period. All this interaction helps to align waking hours and other aspects of our physiology to the 24-hour passage of day and night.
In the latest paper, Partch and her colleagues focused on two core clock components: an enzyme known as casein kinase 1 (CK1) and a protein called PERIOD. Clock-altering mutations in CK1 and PERIOD have been known for many years. In fact, CK1 was discovered in studies of golden hamsters more than 20 years ago after researchers noticed one hamster that routinely woke up much earlier than the others [2,3].
It turns out that the timing of biological clocks is strongly influenced by the rise and fall of the PERIOD protein. This daily oscillation normally takes place over 24 hours, but that’s where CK1 enters the picture. The enzyme adjusts PERIOD levels by chemically modifying the protein at one of two sites, thereby adjusting its stability. When one site is modified, it keeps the protein protected and stable. At the other site, it leaves it unprotected and degradable.
Many of these details had been worked out over the years. But, Partch wanted to drill even deeper to answer an essential question: Why does this process normally take 24 hours, which is remarkably slow biochemically? And, what changes in those whose daily cycle gets cut far short?
To find out, her team performed a series of protein structure and biochemical analyses of the CK1 mutation originally found in hamsters, along with several other clock-altering versions of the enzyme found in organisms ranging from flies to humans. What they’ve discovered is a portion of CK1 acts as a switch. When this switch functions normally, it generates a near-perfect 24-hour cycle by keeping PERIOD’s stability just right. In this case, people easily and correctly align their internal clocks to the daily coming and going of daylight.
If the switch favors a faster breakdown of the protein, the daily cycle grows shorter and less tightly bound to daylight. For these early risers, it’s a constant struggle to adjust to life in a 24-hour world. Though they try to get in sync, these early risers are never able to catch up. Conversely, a switch that favors a slower breakdown will lengthen the clock, predisposing some to be night owls.
Such shifts in clock timing can arise from alterations either to the CK1 enzyme or the PERIOD protein. In fact, people with an inherited sleep disorder called Familial Advanced Sleep Phase Syndrome carry a mutation in the PERIOD protein at one of the places that CK1 modifies. The new work shows that this change makes PERIOD more stable by interfering with the enzyme’s ability to mark the protein for degradation.
One thing that makes the CK1 enzyme so fascinating is that it’s extremely ancient. A nearly identical version of the enzyme to the one in humans and hamsters can be found in single-celled green algae! It’s clear that this enzyme and its function in biological clocks is, evolutionarily speaking, rather special. And at one level, that makes total sense—our planet has operated on a 24-hour clock for the entire span of evolutionary time.
The versions of CK1 that Partch’s team studied here are rare in people. She now plans to study other variations that turn up in humans much more often.
Her discoveries are sure to offer a fascinating view on these internal clocks and, pardon the pun, how they make us all tick. She hopes they’ll lead to new ways to adjust the clock in those with sleep disorders and even the means to reset the clock in people who regularly travel overseas or work the night shift.
Ultimately, Partch would like to tap into the crosstalk between biological clocks and the ability of cells to repair their DNA. She wants to see if clock disruptions have any implications for cancer susceptibility. And yes, now’s a good time to find out the answer.
 Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch. Philpott JM, Narasimamurthy R, Ricci CG, Freeberg AM, Hunt SR, Yee LE, Pelofsky RS, Tripathi S, Virshup DM, Partch CL. eLIFE. 2020 Feb 11;9.
 A mutation of the circadian system in golden hamsters. Ralph MR, Menaker M. Science. 1988 Sep 2;241(4870):1225-7.
 Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS. Science. 2000 Apr 21;288(5465):483-92.
Circadian Rhythms (National Institute of General Medical Sciences/NIH)
Advanced Sleep Phase Syndrome, Familial (Genetic and Rare Disease Center/NIH)
Partch Lab (University of California, Santa Cruz)
NIH Support: National Institute of General Medical Sciences; Office of the Director