As many as 80% of people with opioid use disorder (OUD) have insomnia, and finding the appropriate treatment for them can be a challenge, says Andrew Huhn, associate professor in the Department of Psychiatry and Behavioral Sciences.

Opioids directly affect sleep through the orexin neurotransmitter system that is responsible for wakefulness, the psychiatry researcher explains. If orexin is overactive, a person can have difficulty falling or staying asleep, and cravings for drugs — or other substances, like sugary foods — can kick up. Sleep issues traditionally have been managed by drugs such as benzodiazepines or zolpidem (Ambien). While those interact with opioids and could increase the risk of opioid overdose, they still are sometimes prescribed for people with OUD, he says.

“The other medications prescribed are usually off-label antidepressants or antihistamines that cause drowsiness, but they have been shown not very effective in people with OUD,” Huhn adds. “So patients are either getting something that’s not effective or that might interact with opioids to exacerbate overdose risk.”

Now, with an $18 million grant from the National Institute on Drug Abuse, Huhn and colleagues are launching a three-year, multisite, Phase 3 clinical trial of the sleep medication suvorexant (Belsomra) for people in treatment for OUD. Suvorexant acts as more of an anti-wakefulness drug than as a classic sedative, Huhn explains, and blocks the action of orexin.

The trial, planned for 10 sites including Johns Hopkins, aims to enroll 300 participants who have insomnia and who have been on a stable dose of buprenorphine or methadone for opioid use disorder for at least two weeks. Subjects will be randomized to take 10 mg–20 mg of suvorexant or placebo once a day for eight weeks. They will undergo a polysomnography (PSG) sleep study at the beginning and end of the treatment period to assess improvement in total sleep time. It will also measure how much time is spent awake after the onset of sleep.

The morning following each PSG session, and also during biweekly check-in visits, participants will complete assessments of their mental health (such as depression, anxiety and perceived stress) and any drug-related behavioral factors like impulsivity. Each morning during the study, participants will complete smartphone-based sleep diaries that also record their opioid cravings.

Finding that suvorexant is safe and effective for the treatment of insomnia in people with OUD could spur the Food and Drug Administration to expand its label, Huhn says.

Suvorexant has been studied before in this population. Previous work by Huhn and colleagues, published in Science Translational Medicine, demonstrated that the medication ameliorated sleep disturbance, opioid withdrawal and craving during a buprenorphine taper. It also improved total sleep time by about 90 minutes in patients tapering off opioids, and added about 60 minutes in the post-taper period. Calling these results “far beyond what you would expect from an insomnia trial,” Huhn says that suvorexant also reduced participants’ withdrawal symptoms after they finished taking opioids and reduced their cravings for them.

Previous clinical trials to address sleep in the OUD population have either yielded negative results or been too small to inform insomnia medication, he says.

This study will be the largest of its kind in people with OUD. “It’s focused on improving sleep as a means of improving overall well-being and possibly improving OUD treatment outcomes, which would have a net positive effect on the opioid crisis, he says. “We are also interested in looking at other potential outcomes, such as reduced drug craving.” 

Huhn says that the collected assessments on sleep, drug use, mental health and quality of life will provide a wealth of data that will inform the next wave of studies on the role of the orexin neurotransmitter system in OUD, and also provide a base for future medication development trials.

Johns Hopkins co-investigators for the trial are Jennifer Ellis, Eric Strain, Michael Smith, Suky Martinez and Charlene Gamaldo.